Use of hydroxychloroquine for pre-exposure prophylaxis in COVID 19: debate and suggested future course

KEYWORDS:

• Hydroxychloroquine
• COVID-19
• SARS-CoV-2
• pre-exposure prophylaxis

1. Introduction

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2 has brought the entire world to a halt. With the number of cases and deaths rising rapidly, there is an urgent need for effective preventive and therapeutic interventions. Several characteristics of COVID-19 necessitate the need of a chemoprophylactic agent – high transmissibility and presence of pre-symptomatic transmission and symptomatic carriers, combined with a disproportionately high case fatality rate in elderly patients and those with comorbidities like diabetes mellitus, hypertension, cardiovascular disease, chronic lung disease, malignancy, and obesity [1–3]. Thus, there is a need to protect the vulnerable population, which includes healthcare workers (HCW) as they are at an increased risk of infection and form the backbone of a country’s response to this pandemic. Focus has been directed towards the strategy of ‘drug repurposing/repositioning’- identifying new uses of approved drugs that are outside the scope of their original medical indication, since such drugs are readily available, their safety profiles are well known and their efficacy (or the lack of it) can be demonstrated relatively quickly. Hydroxychloroquine (HCQ) and its congener chloroquine (CQ) have received huge attention both by the scientific community and by the lay public due to its proposed antiviral properties. In a short span of time, this has spiraled into a raging debate over the efficacy of HCQ for prevention/treatment of COVID-19, which have been fueled further by the political attention and controversies surrounding it.

2. Is hydroxychloroquine pre-exposure prophylaxis justified?

Early in the course of the pandemic, in March 2020, the COVID-19 national task force of India issued a recommendation for empiric use of hydroxychloroquine as prophylaxis for HCW involved in care of suspected/confirmed COVID-19 patients and contacts of lab-confirmed cases, later expanded to include frontline workers (surveillance workers, police personnel) involved in COVID-19 activities and all HCW [4]. Evidence in support of use of HCQ is drawn from pre-clinical in vitro studies and a few retrospective observational studies. Studies on Vero cell lines have determined that HCQ when used as pre-exposure prophylaxis effectively inhibits SARS-CoV-2 with a 50% maximum effective concentration (EC₅₀) of 4.51–5.85 µM [5,6]. HCQ inhibits viral entry by modifying the ACE-2 receptor (the receptor used by SARS-CoV-2 for entry into target cells) and terminal glycosylation spike (S) glycoprotein of the virus [6]. Further, HCQ inhibits attachment of the S-protein to ACE-2 and inhibits post-entry steps by increasing pH of endolysosomes [6,7]. A retrospective observational study on HCW in India suggested that consumption of 4 or more weekly maintenance doses of HCQ for prophylaxis was associated with lower risk of contracting COVID [8].

While early in the course of the pandemic, due to limited in knowledge and many unanswered questions, an empiric use of HCQ for prophylaxis may be justified as a prudent approach [9], since it is a cheap, readily available, and relatively safe drug with a favorable pharmacokinetic profile (prolonged half-life, high concentration within lung tissue). However, past experience with other viral infections and evidence generated in recent months has generated considerable doubts and concerns over widespread use of HCQ.

Results from in vitro studies with cell cultures may not be necessarily replicated in in vivo models and clinical studies, as has been observed in other viral diseases. For example, while HCQ and CQ were shown to have an anti-viral effect against filoviruses in vitro, this result was not replicated in in vivo animal models [10]. Similarly, CQ inhibited influenza virus in vitro, but a double-blind randomized control trial (RCT) found no evidence of a protective benefit of CQ against influenza infection in healthy adults [11]. Thus, it may be premature to make clinical decisions and guidelines based on in vitro data.

During the initial months of the pandemic, anecdotal observations that there were no patients with systemic lupus erythematosus (SLE) and COVID-19 led to a hypothesis that chronic HCQ use in these patients may be protecting them. However, this is no longer the case. Results from the COVID-19 Global Rheumatology Alliance, a physician-reported registry have since identified 600 cases of COVID-19 in patients with rheumatic diseases, including 85 with SLE [12]. A nationwide, retrospective-matched cohort study from France with more than 50,000 participants on anti-malarials reported that those exposed to chronic anti-malarials were not protected from hospitalization due to COVID-19 [13]. While this evidence suggests chronic HCQ does not prevent severe COVID-19, there is a possibility that this may be due to insufficient blood levels of HCQ attained with dosing regimens used in these conditions.

Decades of experience of using HCQ for malaria and in rheumatological and dermatological conditions tell us that the drug has a good safety profile, with the most common adverse events being self-limiting gastrointestinal disturbances. Pre-exposure prophylaxis with HCQ has been found to be generally safe; while an RCT among asymptomatic HCW found higher incidence of side effects on HCQ versus placebo (31% versus 21%), the most common adverse events were mild gastrointestinal disturbances including nausea, vomiting, and diarrhea [14].

The most feared adverse effect of HCQ are drug-induced QT interval (QT_C) prolongation and subsequent torsade de pointes (TdP). TdP has been reported only rarely in a few case reports and overdoses. However, the nature of COVID-19 raises some safety issues with use of HCQ. While these concern hospitalized COVID-19 patients receiving HCQ for treatment, they may have significance for pre-exposure prophylaxis, owing to its prolonged half-life (~ 40 days). COVID-19 itself can lead to baseline elevation of QT_C, which is associated with raised inflammatory markers and cardiac troponins, and may be explained by myocardial injury due to direct effects of the virus or due to systemic inflammation [15]. Due to this reason, the QT_C prolonging effect of HCQ has a higher risk of leading to severe adverse events. The risk of prolonged QT_C converting to TdP is further compounded due to risk factors like older age, acute renal failure, and co-administration of drugs like azithromycin and amiodarone. Some studies have reported significant QT_C prolongation with use of HCQ, with critical QT_C (a marker of high risk for TdP) reached in upto 30% patients and premature termination of the drug being common [16–18]. Instances of TdP have been observed in two studies [16,17]. However, in other study cohorts, it has been reported that while QT_C prolongation occurred, it did not lead to arrythmias and drug discontinuation was rarely needed [19,20]. USFDA pharmacovigilance data reports 90 cases of serious cardiac events (17 fatal events) associated with HCQ including QT_C prolongation, TdP, and other ventricular arrythmias [21]. Indian pharmacovigilance data on HCQ prophylaxis reports seven cases of serious side effects with three cases of QT_C prolongation [4]. Serious non-cardiac adverse events have also been noted, the most common events being hepatitis/increased liver enzymes/hyperbilirubinemia [21]. Currently, while it cannot be said with certainty if these numbers represent a significant risk or not, the possibility of the former cannot be ruled out.

These reports establish that risk of serious side effects with HCQ use in COVID-19 is not non-existent, thus raising ethical concerns over its ‘off-label’ use, especially when greater number of people take it in the absence of adequate monitoring. For perspective, a study in HCW in India taking HCQ prophylaxis found that only 21.6% of those with preexisting cardiovascular disease underwent an ECG prior to HCQ intake [22]. People on HCQ prophylaxis who go on to develop COVID-19 later may be vulnerable to the serious side effects of the drug as discussed above, especially the geriatric population, wherein HCQ has not been found effective for viral clearence [23]. The unprecedented coverage received by HCQ in the lay media and its touting by prominent politicians, combined with widespread panic among the population with people desperate for measures to protect themselves has led to rampant self-medication with HCQ. Shortages of HCQ have been reported in many areas, which is very concerning for patients requiring HCQ for disease control including SLE and dermatological conditions like lichen planus, dermatomyositis etc [24]. Discontinuation of HCQ in SLE patients can precipitate disease flares, contributing to morbidity and even mortality; and indeed, physicians treating these patients currently face dilemmas on prescribing/continuing HCQ.

Thus, prescribing HCQ for pre-exposure prophylaxis outside the context of research studies and in the absence of adequate monitoring for adverse events may go against the dictum of primum non nocere.

3. Conclusions and future course

There is a lack of robust studies to support the use of HCQ as a chemoprophylactic agent for pre-exposure prophylaxis. In addition, there is justifiable concern regarding the adverse effects associated with it. The USFDA recently revoked the emergency use authorization of HCQ and CQ for COVID-19 citing results from recent large-scale RCTs demonstrating lack of benefit of HCQ in COVID-19 patients, combined with the ongoing reports of serious cardiac events. The question of prophylaxis, however, remains open. Presently, use of HCQ for COVID-19 prophylaxis should be limited to only in the context of research studies. While it has certain good characteristics – favorable pharmacokinetics, low cost, readily available, in vitro evidence of benefit; the tendency to extrapolate them as surrogate markers for clinical efficacy may lead to a false sense of security and be counterproductive in the long run and thus should be avoided, especially for mass chemoprophylaxis, till more robust evidence is generated.

4. Expert Opinion

The issue of HCQ pre-exposure prophylaxis has immense importance with regards to the COVID-19 pandemic as an effective agent can help curb spread of the pandemic, thus generating good quality evidence should have top priority. One pertinent aspect is the effective dosage of HCQ that would be required for pre-exposure prophylaxis. While this has been estimated by one study using in vitro data, they used an EC50 of 0.72 µM derived from a treatment experiment [55], whereas pre-treatment experiments simulating pre-exposure prophylaxis have found a much higher EC50 of 4.51–5.85 µM [55,66]. It should also be noted that these values are for extracellular drug concentrations in the culture media, thus extrapolation should be made to in vivo plasma concentration and not lung tissue concentration. Calculations of dosing regimens need to take into account these factors. It is likely that currently used dosing regimens may be inadequate to provide a benefit, although higher doses may lead to significant safety concerns. Several trials studying pre-exposure prophylaxis using HCQ for COVID-19 with varied dosing regimens are currently ongoing (Table 1), including large-scale multi-centre trials such as the COPCOV trial. Most of these trials focus on HCWs. As a couple of observational studies suggest there may be potential benefit, a randomized controlled trial can be conducted at the community level to obtain conclusive evidence. For example, a double-blind trial targeting asymptomatic population of COVID-19 hotspot areas or household contacts of COVID-19 confirmed cases may provide valuable insights into use of HCQ for mass prophylaxis. Results from such trials will provide a definitive answer to this important question.

Table 1. Ongoing clinical trials for pre-exposure prophylaxis with hydroxychloroquine for prevention of COVID-19

S. no.	Trial no.	Trial name	Methodology	Dose of hydroxychloroquine
1	NCT04352946	HEalthcare Worker pROphylaxis against COVID-19 (HERO trial)	Randomized, double blind, placebo-controlled	400 mg once daily for 60 days
2	NCT04336748	HCQ for Primary Prophylaxis Against COVID-19 in Health-care Workers	Randomized, double blind, placebo-controlled	200 mg once daily for 4 weeks
3	NCT04340349	Low-dose Hydroxychloroquine and Bromhexine: a Novel Regimen for COVID-19 Prophylaxis in Healthcare Professionals (ELEVATE)	Randomized, double blind, placebo-controlled trial	200 mg daily for 2 months with 8 mg of Bromhexine every 8 hour for 2 months
4	NCT04354870	COVID-19 PrEP HCW HCQ Study	Open-label, non-randomized, placebo-controlled trial	Loading dose: 600 mg, oral, 1 day Maintenance dose: 200 mg, oral, daily, for 90 days
5	NCT04334928	Randomized Clinical Trial for the Prevention of SARS-CoV-2 Infection (COVID-19) in Healthcare Personnel (EPICOS)	Randomized, double blind, placebo-controlled trial	200 mg once daily for 12 weeks
6	NCT04371523	Hydroxychloroquine to prevent COVID-19 Disease Amongst Healthcare Workers (PROVIDE)	Randomized, double blind, multi-center, stratified, placebo-controlled trial	400mg PO BID on day 1 400mg PO weekly for 2 months
7	NCT04353037	PATCH 2&3: Prevention & Treatment of COVID-19 With Hydroxychloroquine	Open label, multi-arm, placebo-controlled randomized trial	Sub-Study 1: COVID-19 patients in self-quarantine. 400 mg bid for 2 weeks Sub-Study 2: Asymptomatic health care worker prophylaxis. 600 mg once a day for up to 2 months
8	NCT04446104	A Preventive Treatment for Migrant Workers at High-risk of COVID-19	Randomized, Open-label Prophylaxis Trial	400mg loading dose, followed by 200mg daily for 42 days
9	NCT04328467	Pre-exposure Prophylaxis for SARS-Coronavirus-2	Randomized, double blind, placebo-controlled trial	Weekly: 400 mg once, followed by 400mg 6-8 hours later, then 400mg weekly up to 12 weeks Twice weekly: 400mg once, followed by 400mg 6-8 hours later, then 400mg twice weekly up to 12 weeks
10	NCT04333225	Hydroxychloroquine in the Prevention of COVID-19 Infection in Healthcare Workers	Non-randomized, open label clinical trial	400 mg twice a day on day 1 followed by two 200 mg tablets once a week for 7 weeks.
11	NCT04347889	Preventing COVID-19 in Healthcare Workers With HCQ: An RCT	Open label, placebo-controlled, randomized trial	Oral loading dose of 800 mg followed by once weekly 400 mg for 3 months
12	NCT04435808	Efficacy of Hydroxychloroquine Prophylaxis for Health Care Workers at High Risk for COVID-19	Non-randomized, open label clinical trial	Loading dose: 600 mg once for the first day Maintenance dose: 200 mg, daily
13	NCT04391127	Hydroxychloroquine and Ivermectin for the Treatment of COVID-19 Infection	Randomized, double blind, placebo-controlled trial	400 mg 12 hourly for one day. Subsequently 200 mg 12 hourly for 4 more days.
14	NCT04389359	PROphylaxis for paTiEnts at Risk of COVID-19 infecTion (PROTECT)	Open label, randomized clinical trial	Dialysis patients: 600mg weekly in divided doses, given as 200mg after each dialysis session. Non-dialysis patients: 400mg twice daily for two days, then 400mg weekly.
15	NCT04381988	A Study of Hydroxychloroquine vs Placebo to Prevent COVID-19 Infection in Patients Receiving Radiotherapy	Randomized, double-blind, placebo-controlled phase II clinical trial.	400mg daily
16	NCT04410562	Hydroxychloroquine Efficacy and Safety in Preventing SARS-CoV-2 and COVID-19 Disease Severity During Pregnancy (COVID-Preg)	Randomized, double-blinded, placebo-controlled multicenter clinical trial.	400 mg/day for three days, followed by 200 mg/day for 11 days
17	NCT04318015	Hydroxychloroquine Chemoprophylaxis in Healthcare Personnel in Contact With COVID-19 Patients (PHYDRA Trial) (PHYDRA)	Triple blinded, randomized controlled trial	200mg per day for 60 days.
18	NCT04352933	PROLIFIC Chemoprophylaxis Trial (COVID-19)	Randomized, double-blind placebo-controlled trial	Daily dosing: Loading phase - 400mg BD for 2 days; Maintenance Phase - 200mg OD for 3 months Weekly dosing: Loading Phase - 400mg BD for 2 days; Maintenance Phase - 400mg weekly for 3 months.
19	NCT04303507	Chloroquine/Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting (COPCOV)	Randomized, double blind placebo-controlled trial	Loading dose of 10 mg base/kg followed by 200 mg will be taken for 3 months
20	NCT04341441	Will Hydroxychloroquine Impede or Prevent COVID-19 (WHIP COVID-19)	Randomized, double blind placebo-controlled trial	Daily: 200 mg OD following day 1 dose of 400 mg. Weekly:6.5 mg/kg per dose (maximum of 400 mg) weekly

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.