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Hydroxychloroquine and COVID-19 – A narrative review

COVID 19 infection is unarguably the worst pandemic of this century. Till date there is no promising drug and vaccine available to treat this deadly viral infection. In the early phase chloroquine phosphate and hydroxychloroquine sulphate have been used to fight this illness on the basis of handful observational and small randomized and small-randomized studies. The paucity of clinical evidences of an unequivocal beneficial effect of chloroquine and hydroxychloroquine on COVID-19 has resulted in the passionate use of the drug for moderate to severe cases only and stimulated the need for large clinical trials for this and other molecules. In this review, we describe in brief the mechanism of action, the clinical studies, factors for cardiac toxicity, guidelines and future directions for hydroxychloroquine use in management of COVID-19 infection.


Introduction
Novel Coronavirus disease  infection has emerged as an pandemic which in a short window of four months has affected more than 4 million people around the world. 1 The index case of COVID-19 which was reported in the penultimate days of past year from Wuhan city, Hubei province, People's Republic of China, and thereafter has spread like wildfire across 190 countries.
Corona viruses (SARS-COVID) are crown shaped, positive sense single stranded RNA viruses belonging to Coronaviridae family. They are enveloped viruses. They most commonly inhabit in avian and mammalian species. The present iteration of the virus owes its origin from bats while the previous versions had emerged from cats in 2002-04 and from camels in 2012 respectively.
With the myriad number of patients affected the virus has already taken a toll on the health system and resources across the globe. Not only hospitals have been overwhelmed with patients and the Intensive care units (ICU) filled up to the brim but also many frontline health workers including nurses and doctors succumbed to the illness. Hence there is imminent need to find a potential treatment for this deadly illness. At present there are various promising therapies being tried including Remdesivir, Lopinavir/ritonavir, Chloroquine (CQ) and Hydroxychloroquine (HCQS), Umifenovir (Arbidol), tocilizumab and plasma therapy. 2 In this review we describe in brief the pharmacology, the trials, regimens, adverse effects and guidelines related to hydroxychloroquine/chloroquine.

2.
Chloroquine e a precursor to HCQS Chloroquine (CQ) was first the drug to be evaluated for efficacy against SARS-CoV2 infection with severe acute respiratory syndrome. The antiviral, anti-inflammatory and immunomodulatory properties of CQ led to clinical testing of this drug as an experimental treatment in China and on the basis of initial success from small results it was advocated by the National Health Commission guidelines of the people's Republic of China. 3 This document established the use of chloroquine nationwide for patients with COVID-19, at a recommended adult dose of 500 mg twice per day for a maximum of 10 days.
Chloroquine (CQ) is a widely utilized drug for prophylaxis and treatment of Malaria. Hydroxychloroquine (HCQS) is a hydroxyl derivative of chloroquine. It is more water soluble, less toxic and has fever side effects than chloroquine (Table  1). 4 CQ and HCQS are metabolized by cytochrome P450 in the liver, however 50% of the metabolites excreted by kidney without any modification. CQ has large volume of distribution and a tendency to accumulate in tissues at higher levels compared with plasma concentration. The elimination halflife of CQ is between 20 and 60 days. 5e7 The toxic dose of CQ in adults is about 5 gram. 5 Some prior studies had hinted at antiviral activities of the molecule with the drug hindering fusion of virus and glycosylation of it's receptors. 8,9 In preclinical studies, chloroquine was found to have invitro activity against COVID-19. 10 Based on the data of 100 patients in over a dozen trials across 10 centers, where chloroquine resulted in radiological clearing and shortening the hospital course, the national health commission approved the use of at chloroquine. 11 Borba et al tested two doses of CQ in COVID-19-600mg twice daily for 10 days and 450 mg twice daily for a day, once daily thereafter for 4 days. 12 There was no difference in lethality of disease amongst the two doses of CQ. Rather the high dose groups had more QT prolongation questioning the rationale use of high doses.
The Chinese health commission guideline initially recommended the dose of CQ 500 mg twice per day to the maximum course of 10 days but this regimen was more aggressive. Toxic effects of chloroquine were retinopathy and immunosuppression in early studies. The treatment guidelines were amended in late February, curtailing the maximum course duration to 7 days. 13 They also recommended lower dose for patients less than 50 kg and contraindicated the drug in pregnancy. Though chloroquine is recommended in China for the treatment of Covid-19, but high-quality data are lacking to show whether it or hydroxychloroquine is safe and effective for this indication. Recently, the US food and Drug Administration (USFDA) has issued a caution and restricted the use of CQ for the management COVID-19 outside of hospital or a clinical trial due to the risk of arrhythmia. 14

3.
HCQS e first among equals HCQS is the less toxic derivative of chloroquine and has been utilized to treat COVID 19 as an alternative. The molecule was first synthesized by Hans Andersag in 1934 as an analogue of chloroquine (CQ) with higher water solubility.
In vitro studies have shown that HCQS can inhibit virus entry, transmission and replication. 15,16 The mechanism of action include raising the PH of cellular endosomes to inhibit viral entry as well as replication and glycosylation of virus surface receptors ACE-2. 17 Apart from antiviral activity, miscellaneous actions of HCQS include immune modulation,anti-inflammatory properties and regulation in pro inflammatory cytokines e.g. tumor necrosis factors (TNF), interleukin (IL)1 & 6 and antioxidant activities. In severe or critical illness cases of Covid-19, a cytokine storm exists and effects the prognosis of COVID-19 disease. 18 The immunomodulatory effect of HCQS can be the additional avenue for mechanistic benefit. In fact, IL 6 antibody blocker-tocilizumab, interferon-l and transfusion of convalescent plasma have been applied to counteract the cytokine storm.
HCQS is a cheap drug, easily available and seems to be safe too. The drug is not recommended for prophylaxis in children under 15 year of age.

Clinical data of HCQS in COVID
On the basis of different observational and some randomized trial ( i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 7 ( 2 0 2 0 ) S 1 4 7 eS 1 5 4 lesser number of cough days were observed in the HCQS group (2.0 ± 0.2 days vs. 3.1 ± 1.5 day) and a significant decline in the radiological progression. 19 The French collaborative studies led by Gautret et al subsequently demonstrated the efficacy HCQS in combination with azithromycin (Az) in attenuation of the viral load in patients with COVID 19. 20,21 In the first prospective open level randomized control trial, hospitalized COVID 19 patients age >12 years were included. The principal exclusion criteria included prior allergy to HCQS, Retinopathy, G6PD deficiency and risk of QT prolongation. This study revealed that HCQS þ Azithromycin (AZ) combination was potent in clearing viral load from nasopharyngeal site in only three to six days. A significant difference was observed between HCQS-treated patients and controls starting as early as day 3 post-inclusion. The second one was a pilot study in which 80 patients were enrolled and got 200 mg HCQS three times a day for 10 days and azithromycin 500 mg on day 1, 250 mg on days 2e5. The viral load decreased significantly with therapy. These three preliminary studies pitchforked hydroxychloroquine into the limelight for reduction pf duration of hospital stay and improve the prognosis of COVID-19-related pneumonia.
Jun et al more recent in a study from China in individuals with COVID-19 found no difference in the rate of virologic clearance at 7 days with or without 5 days of hydroxychloroquine, and no difference in clinical outcomes (duration of hospitalization, temperature normalization, radiological progression). 22 Tang et al conducted a randomized open label study in 150 patients hospitalized for COVID-19. 23 The addition of HCQS to the standard of care did not result in a higher negative viral seroconversion. However, there was alleviation of clinical symptoms compared to standard care arm who were not receiving antiviral treatment. The possible mechanism of improvement was through anti-inflammatory effects. Adverse effect of high dose regimen (1200 mg/d) were seen in 30% but serious events were not different.
Million et al tested 1061 COVID-19 patients treated with HCQS þ AZ combination for three days and eight days of follow-up the majority of patients had relatively mild disease at admission. Under these conditions, the treatment avoided worsening of the disease, as only 10 patients (0.9%) were transferred to the intensive care unit, but it also attenuated death rate, as only eight (0.75%) patients died. The drug also impaired persistent viral shedding. 24 Mahevas et al analyzed data of 181 patients hospitalized with COVID 19 pneumonia. In this study, 20.2% patients from HCQS group were transferred to the intensive care unit or died with in 7 days vs 22.1% in the non HCQS group. In the HCQS group 27.4% patients developed acute respiratory syndrome and 9.5% showed electrocardiogram changes which leads to discontinuation of drug. 25 Hence, the trial failed to demonstrate the usefulness of HCQS 600mg/d in COVID pneumonia.
Molina et al in their retrospective analysis of hospitalized COVID-19 patients, did not find any impact of HCQS use either with or without azithromycin, on the risk of mechanical ventilation. However, the use hydroxychloroquine as alone was associated with high mortality. 26 Joshua Gileris et al studied HCQS in 1376 patients, during a median follow-up of 22.5 days. 27 About 811 (58.9%) patients received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death.

Pitfalls
The trials and studies were heterogenous in their inclusion criteria, drug dosing, duration and end points. Most of the studies had small sample size thus lacking sufficient power and leading to possible exaggeration of treatment effect. Many of the studies of COVID 19 tended not to include critically ill patients who could be receiving several other medications as well as having concomitant organ dysfunction like kidney and liver hepatic which both of which can alter the drug clearance from body leading to toxicity. Many studies have included virologic clearance and viral load as endpoints but the clinical significance of high viral load vis-a-vis cytokine storm in critically ill patients in seclusion is not yet known. Lack of a placebo arm and abundance of non-randomized studies is also of concern. Few of the studies discussed above are still in preprint (undergoing peer review; available from medRxiv. org) and yet to be published. The last and not the least, the issue of cardiovascular safety is discussed below.

HCQS and cardiovascular safety
Both HCQS and CQ have the tendency to mildly prolong QT interval on chronic use. 28 In critically ill patients, with renal and hepatic dysfunction these toxic effects would be more likely. This increase in QT prolongation serves as an indirect marker of risk of polymorphic ventricular tachycardia (VT) or torsade's de pointes with the drug. Since, such arrhythmia's can be life threatening drug induced QT prolongation becomes a pivotal parameter of safety. A caveat to be remember is that on a miniscule fraction of those with QT elongation will develop VT and arrhythmic mortality. 29 The QT interval corrected to the underlying heart rate is provides the most appropriate value and is termed as corrected QT interval (QTc). It can be calculated manually or the newer generation devices provide automated values.
Since both these drugs have the potential to prolong QT interval, a baseline electrocardiography (ECG) is essential prior to starting these drugs. Other precautions include frequent monitoring of hematological parameters (RBC, WBC and platelet counts), measurement of serum electrolytes, blood glucose (because of hypoglycemic potential of HCQS) and hepatic as well as renal functions. Co-administration of other drugs known to prolong the QTc interval must be avoided (Fig. 1). Azithromycin a drug used in the treatment COVID-19 also has the potential of QT prolongation. 30 In clinical studies with COVID -19, the rate of QT prolongation varies any where between 10% and 20% (Table 3).   Moreover, addition of azithromycin to HCQS increased the risk of QTc prolongation. This was precisely the case in the study by Chorin et al who found that 11% patient had QTc >500 with the combination while 30% had QTc increase >60 ms. 32 Mecuro et al provided more precise comparison between monotherapy & combination therapy. 32 The combination therapy experienced greater median change in QTc (23ms vs. 5.5ms), greater proportion of patients with QTc >500 (21% vs.19%) & higher fraction of subjects with increase in QTc > 60ms(13% vs. 3%). In corollary, recent data emerging in Fig. 1 e Commonly used drugs causing QT interval prolongation on ECG.  the second week of May found higher in hospital morality with combination therapy in the New York state which was the COVID epicenter of USA. 33 The USFDA too has issued a warning against HCQS use outside a hospital setting or clinical trial setting. 13 Hence, it is also essential to perform ECG daily if QTc is 450e500 msec. Chloroquine and HCQS should not be used concurrently with lopinavir/ritonavir and Remdesivir for anticipated QTc prolongation. Table 3 lists the cardiovascular and other side effects observed in different studies.
Known hypersensitivity, retinopathy, porphyria, epilepsy, pre-existing maculopathy, pregnancy, G6PD deficiency, recent myocardial infarction and QTc >500 msec are the major contraindications to HCQS. Chloroquine however is not contraindicated in pregnancy. High HCQS doses >600 mg BID were also predictive of prolongation of QTc intervals. Higher HCQS doses need close monitoring to ensure cardiac safety and are best avoided.
A variety factors are known to increase risk of drug induced ventricular arrhythmia like female sex, structural heart disease, electrolyte disturbances, congenital long QT syndromes, concomitant QT prolonging drugs and hepatic/renal failure. 34 A risk score has been derived and validated by Tisdale et al, for prediction of drug associated QT prolongation (Table 4).

7.
Guideline recommendation HCQS is currently an essential part of treatment regimen in almost all of the recommendation across the globe as depicted in (Table 5). However, it should not be used as stand alone therapy in the management of COVID-19, as there is paucity of unequivocal data on effectiveness. The dose and duration varies across the globe and one needs to follow local guidelines.

Yin and Yang of managing a pandemic
The novel corona virus has posed a unique challenge by spreading across all continents of globe (except Antarctica) in a span of 5 months affecting more than 4 million people.
Simultaneously it has caused >3,00,000 casualties worldwide including frontline health workers. The rapid spread and the lack of an approved drug against the virus has fueled the search for identifying the potency of currently plethora of  i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 7 ( 2 0 2 0 ) S 1 4 7 eS 1 5 4 S152 antiviral drugs against COVID-19. Because of both antiviral and immunomodulatory effects, both CQ & HCQS were tested against COVID-19. Though small and non-randomized, initial few studies from February and March provided a hope among both clinicians and patients alike against the massive fear and despair generated by the pathogen globally. The drugs were approved by major health care associations and national societies in varying doses. The wait for larger randomized studies had to be rationalized against the rising fatalities and hospitalizations due to the virus. Another dilemma posed by the pandemic is choosing between offering immediate relief and generating data for medical research. 12 More recent data has highlighted the cardiotoxicity and increased mortality caused by HCQS. Pending the discovery of an effective agent or vaccine we will have to continue the compassionate use of the drug for treatment of COVID-19. However, careful selection of patients at who are at low risk of QT prolongation, prescribing lower doses and avoiding concomitant drugs which also prolong QT are measures to the tilt the benefit risk ratio in favor of HCQS.

Future directions
The WHO has announced the phase III/IV SOLIDARITY clinical trial to find an effective treatment of COVID-19 in collaboration with 100 countries including India. 42 Four investigational therapies are being tried e Remdesivir, Lopinavir/ritonavir, HCQS and interferon beta 1. Rigorous search for a potential cure is on. A ClinicalTrials.gov search using keywords "COVID-19" or "SARS-CoV 2" & "treatment" on 18th May 2020 yielded 1095 results. Out of them 593 studies are actively recruiting patients for COVID-19.

Conclusion
COVID-19 has emerged as a rapidly spreading and worst pandemic of the century till date. HCQS due to it's antiviral and immunomodulatory properties has been tried for COVID-19 infections. Initial positive data form multiple small studies led to an enthusiasm and endorsement of the drug by various guidelines. More recent studies have questioned the role of the drug and highlighted the cardiotoxicity especially when combined with azithromycin. Additional research is underway and until emergence of more data the passionate use of HCQS should continue under proper surveillnce.