Experts at the University of Huddersfield are urging caution over claims that widely-available antimalarial drugs could be a “magic bullet” to prevent and cure CoVid-19. And the medicines can – if used rashly – have serious side effects.
Although there have been some encouraging signs from small-scale preliminary trials of the drugs chloroquine (CQ) and hydroxychloroquine (HCQ) when administered to coronavirus patients, the results are preliminary and should be treated with care, argue Dr Syed Shahzad Hasan and Dr Hamid Merchant.
They are co-authors – in collaboration with a pharmacist from Malaysia, Chia Siang Kow, of the International Medical University in Kuala Lumpur – of a new article in the British Journal of Pharmacy. It is freely available for all to read online.
The authors chart the excitement in press and social media over claims that CQ and HCQ could be effective CoViD-19 treatments.
But they also report how this had led to hoarding and therefore shortages of the drugs – available over the counter in some countries.
There have been reports of deaths in some parts of the world because of inappropriate self-use of CQ. And while the drugs have a good safety record, they can have seriously adverse side-effects, including loss of vision and fatal cardiovascular problems.
“It is the duty of pharmacists and other healthcare professionals to monitor the proper usage of these antimalarial drugs,” states the British Journal of Pharmacy article.
As the evidence currently stands, write the authors, CQ/HCQ cannot be used as a general treatment for all CoViD-19 patients.
“Its use should be restricted for the treatment of CoViD-19-associated pneumonia in severely-ill patients only under a trial or clinical supervision of a licenced practitioner and close cardiac monitoring.”
The article – titled Is it worth the wait?
Should Chloroquine or Hydroxychloroquine be allowed for immediate use in Covid-19? – includes a bullet point list of key points and recommendations.
It is stated that “there is no evidence to support the mass use of CQ/HCQ to prevent the infection in public at large, therefore these drugs cannot be recommended for general use by the public to protect from acquiring SARS-CoV-2 infection.
Social isolation and quarantine measures are still appropriate to control the infection until a reliable preventive option becomes available, for instance a vaccine”.
The authors also point out that there had been only limited use of CQ/HCQ in clinical settings and no conclusive, randomly-controlled trials are yet available.
It is argued that “there is a need for an open-access central repository where clinicians can record the use/outcomes of CQ/HCQ or other pharmacological interventions for the thorough scrutiny of the data by the global scientific community”.
The warnings sounded in the British Journal of Pharmacy article have since been reinforced by the U.S. Food and Drug Administration in a webpage that cautions against use of hydroxychloroquine or chloroquine for CoViD-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems.
Meanwhile, Dr Merchant, who is the Subject Leader at the University of Huddersfield’s Department of Pharmacy, and Dr Hasan, who is a Senior Research Fellow, continue to research and write about the latest developments in the coronavirus pandemic.
Analysis of potential treatments for CoViD-19
Another article by Dr Merchant published in the British Medical Journal analyses a World Health Organisation trial of four potential treatments for CoViD-19.
The article – also freely available online – is an 11-point analysis of the project. Dr Merchant acknowledges that “the launch of WHO’s Solidarity Trial came as good news for many, the public in general and clinicians in particular who are at the frontline to manage these crises”.
But he provides a detailed critique of the drugs that are and are not included in the WHO trial.
And he concludes that:
“There are as many as seven variants of human coronavirus that have been reported and there have been reports of CoV-2 being further genetically evolving during the current CoViD-19 outbreak.
If the global Solidarity Trial will not offer all drug options/combinations across the world in a single co-ordinated trial, we fear that the data from different countries may not be directly comparable to draw any meaningful comparison”.
Key Research Question:
What is the evidence for and risks of using hydroxychloroquine (HQ) as a treatment and prophylaxis for SARS-CoV-2?
Key Messages from the Evidence Summary
- The evidence of HQ effectiveness in treating COVID-19 illness is limited. Although there is plausible in vitro activity of HQ against COVID-19, there is equivocal in vivo data across observational studies and small randomized controlled trials with significant methodologic concerns.
- There is no evidence for HQ for use as prophylaxis for COVID-19 illness. There are multiple randomized trials underway to explore this in health care workers and close contacts to known cases.
- HQ risks, particularly when used for patients with cardiopulmonary compromise due to COVID-19 infection, include the potential for serious clinical and laboratory adverse effects, potential drug interactions, and carry a risk to children if unintentionally ingested.
The committee recommended prioritizing use of HQ for patients with rheumatologic disease, and those in COVID-19 randomized controlled clinical trials and recommended removing HQ from COVID-19 order sets.
The committee felt strongly that any off-label use of HQ requires the prescribers’ careful consideration of risk/benefit, consultation between experts and attending physicians, and documenting a verbal consent from patients after discussion of the current state
of evidence of benefit and harms. This reflects the content of an Ethics consult that was done in the context of this review. Committee members noted that if used outside the context of clinical trials, adverse events of HQ for hospitalized patients should be documented/collected by clinicians through the AHS Reporting and Learning System for Patient Safety at https://insite.albertahealthservices.ca/tools/rls/Page1820.aspx.
One committee member felt strongly that HQ should not be used outside the context of a clinical trial. It was noted that the HOPE Alberta COVID trial is collecting information on the safety of HQ at 7 and 30 days in trial participants.
There were concerns raised by the Divisions of Infectious Diseases regarding continuation of the recommendation for mandatory Infectious Disease (ID) consult or approval, because of the variation in opinion of ID physicians on off label investigational therapies in COVID-positive patients.
Therefore, we recommend to remove this from the existing process and instead leave it as an option on a case by case basis reflecting usual clinical considerations. Since an option of using HQ for hospitalized patients will still exist, it is important to prescribers to determine the risk of adverse events prior to initiation.
This includes ensuring physicians are aware of and mitigate the risk of prolonged QTc (including ordering baseline ECG, and assessing drug interactions with patient’s existing medications) and hypoglycemia. Pharmacy Services will be in a position to assist with the drug interaction check.
The committee also felt that the additional safety concerns that exist for azithromycin and HQ, while specifically note in literature because these have been recommended for COVID19 in the past, are similar for all macrolides as the QTc prolongation is a class effect (i.e. same would happen with clarithromycin or erythromycin).
With respect to prophylaxis, there was agreement with the recommendation to restrict use of HQ for prophylaxis to only within clinical trials as there is no existing evidence to support benefit, and there are concerns with increased household use of hydroxychloroquine given concerns around risk and toxicity to children who might unintentionally access this within the home setting.
- Hydroxychloroquine is not currently recommended to be used as prophylaxis for COVID- 19 outside clinical trials, given the lack of established benefit to counterbalance potential harms, and no existing data on prophylaxis.
- Given the significant increased risk of QT prolongation and cardiac arrhythmias, HQ should not be used with azithromycin or other macrolide antibiotics unless in the context of a clinical trial. These medications should also not be used sequentially given very long half-lives and continued QT prolongation risk.
- As there are limited supplies of hydroxychloroquine within AHS, and concerns may eventually arise with supply in Alberta’s community pharmacies, its use should be prioritized to those patients who are on it for chronic rheumatologic conditions, where there is stronger evidence of benefit.
- For patients with COVID-19 disease, in both the hospital and the community, preference for use of HQ as treatment is given to those enrolled in clinical trials investigating the effects of HQ in treating and preventing severe COVID-19 illness.
- Off-label prescribing of hydroxychloroquine for treatment of COVID-19 positive inpatients should only be performed after careful consideration of the potential harms, consideration of expert consultation as needed (e.g., Infectious Disease, Respiratory Medicine, and General Internal Medicine) and discussion between the Most Responsible Physician and the patient.
- If all criteria in #5 are met and the decision is made to use HQ
- The use of a risk stratification tool (e.g. Tisdale et al, 2013) to access the risk of QTc prolongation must be considered when evaluating the benefit vs harm of using HQ as treatment in SARS-CoV-2 patients.
- A drug interaction check between HQ and the patient’s medications must be completed using the website https://www.covid19-druginteractions.org/ or a suitable alternative. Pharmacy Services can assist with performing the drug interaction check.
- While the patient is on HQ, baseline and intermittent ECGs to assess the corrected QT (QTc) interval during treatment should be considered depending on the patient’s baseline risk.
- Adverse events with respect to off-label use of HQ for inpatient treatment should be documented and reported by clinicians through the AHS Reporting and Learning System for Patient Safety at https://insite.albertahealthservices.ca/tools/rls/Page1820.aspx.
- These recommendations will be updated as the published data evolves.
Summary of Evidence
Literature for this rapid review was gathered in a search strategy performed by Knowledge Resource Services (KRS) in AHS, pulling from a pragmatic search of the COVID-19 literature, as well as through medication safety sources (e.g.: LexiComp).
Limitations to this review are the lack of available scientific peer reviewed evidence on this topic for COVID-19 and there may be evidence from the SARS and MERS experience that was missed by this strategy. A total of 61 references were included in this review. Inclusion/exclusion criteria can be found in the Appendix.
What is the evidence that HQ is effective as a treatment for COVID-19? In Vitro
Both chloroquine (CQ) and HQ have been shown in vitro to inhibit the growth of coronavirus (Keyaerts et al., 2004; Liu J et al, 2020; Vincent et al., 2005; Kono et al., 2008; Yao et al., 2020; Wang et al., 2020). Yao (2020) and Wang (2020) are already referenced in the Alberta Health Services (AHS) antimicrobial recommendations document (AHS, 2020). In summary, in vitro studies show a plausible role of HQ in the treatment of SARS-CoV-2.
In vivo studies in mice have also shown that CQ improves survivability in mice infected with human coronavirus (Keyaerts et al., 2009). With respect to human studies, the first clinical trial data became available mid-March from an open label nonrandomized trial, looking at the efficacy of 600 milligrams of hydroxychloroquine twice a day (plus/minus azithromycin) in reducing nasal swab viral burden by polymerase chain reaction (PCR) positivity in a cohort of 20 patients.
At days 3 and 6 post-therapy, PCR was negative in 50% and 70% of the treated patients, respectively, compared to 6.3% and 12.5% in the untreated group (Gautret et al., 2020a). No clinical outcomes were reported, and patients with severe illness in the HQ arm were censored from the data after ICU admission.
A small pilot randomized controlled trial in China (n=30) showed no difference in virologic or clinical patterns between HQ treated and untreated patients (Chen J, et al, 2020). A preprint randomized parallel-group trial of 62 patients reported that patients in the treatment arm (5-day HQ 200mg b.i.d.) had a significantly shortened body temperature recovery time (3.2 days [1.3 SD] vs 2.2 days [0.4 SD]; p=.0008]) and cough remission time (3.15 days [1.5 SD] vs 2.0 days [0.2]; p=.0016) and improved pneumonia (80.6% vs 54.8%) (Chen Z et al, 2020).
Notably, the original trial registered for this study included a sample size of 100 per group, with only 31 patients per group being reported (Chinese Clinical Trial Registry (ChiCTR), identifier: ChiCTR2000029559).
In summary, these studies provide some preliminary evidence that HQ may be effective in treatment of COVID-19; however, severe limitations and criticism of the Gautret et al (2020a) study are well known (Dahly D, Gates S & Morris T, 2020; Frie, K, & Gbinigie K, 2020; Kim et al, 2020; Lowe D, 2020; Retraction Watch, 2020; Yazdany & Kim 2020), and the Chen study was underpowered. Thus further evolution of this evidence is required.
Current State of Recommendations in Other Jurisdictions
Recommendations for the use of CQ/HQ in SARS-CoV-2 patients have been released beginning in China with respect to pulmonary disease (Dong et al., 2020, Gao J, Tian Z & Yang X, 2020; Liang et al., 2020) but there are recommendations in support of its use available internationally, including an Emergency Use Authorization issued by the US FDA on March 28, 2020 (Hinton, 2020, US FDA 2020a; US FDA 2020b).
To date, recommendations are based on these in vitro data, limited and weak human studies and physician opinion rather than on clinical trial evidence. As such, recommendations for the use of HQ in SARS-CoV-2 patients would have to be made in the absence of high-quality clinical trial evidence at this time. Recently released guidelines for COVID-19 therapy from the Infectious Diseases Society of America,(IDSA, 2020) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach concluded that the currently available best evidence failed to demonstrate or exclude a beneficial effect of HQ on the clinical progression of COVID-19, noting that current trails assess only indirect outcomes. Very high risk selection bias was noted in the virologic outcomes described fro HQ plus azithromycin use. Two studies described significant QT prolongation in 10 of 95 patients (Chorin et al, 2020; Molina et al, 2020).
What is the evidence that HQ is effective as a prophylaxis for COVID-19?
As of April 13, 2020, there are no available data from randomized clinical trials, cohort or observational studies to inform clinical guidance on the use, dosing, or duration of CQ or HQ for
prophylaxis of SARS-CoV-2 infection (Clinicaltrials.gov, 2020). A document circulating on Twitter indicates that HQ is being used for COVID-19 prophylaxis in India, using its purported benefits as a treatment as the rationale for prophylaxis (Bargahva, 2020). There is insufficient evidence on the effectiveness of HQ as a prophylactic for COVID-19.
What are the risks of using HQ as prophylaxis or as treatment for COVID-19?
In addition to the fact that RCTs are lacking, making it difficult to quantify risks in this specific uninfected population, the risks for HQ prophylaxis for SARS-CoV-2 include the following:
- Acute adverse effects may include serious clinical and laboratory features, including prolonged QTc and hypoglycemia.
- Multiple potential drug interactions with patient’s therapeutic medications.
- Risk of pediatric morbidity and mortality with increased unintentional exposures in the home if used widely for prophylaxis.
Safety considerations for the use of CQ, HQ and AZM and other macrolide antibiotics in the management of SARS-CoV-2 infections identified the potential risks of treatment using CQ/HQ to include QTc prolongation (Chorlin et al, 2020), particularly in patients with pre-existing cardiac disease or if used in combination with AZM, as well as other known risks associated with these drugs including hypoglycemia (Unübol M et al, 2011), drug-drug interactions (Somer M et al, 2000) and neuropsychiatric effects (Bhatia 1991; Das P et al, 2014).
Evidence of adverse events is now available, including a preprint retrospective study that reported significant QTc prolongation (p<.001) in patients treated with a combination of HQ/Azithromycin, with the QTc in 11% patients increasing to >500ms (Chorin, E et al, 2020). In this study, both baseline QTc and QTc >460ms were not reliable predictors of extreme QTc prolongation in this preliminary work. Risk of pediatric morbidity and mortality with unintentional exposures is also concerning (Smith & Klein-Schwartz, 2005).
With respect to CQ, a parallel, double-blind randomized trial in Brazil on CQ as treatment for SARS-CoV-2 was required to shut down recruitment to the high dose arm (CQ 600mg b.i.d. for 10 days (total CQ=12g) due to fatal cardiac complications (13.5%) (Silva Borba et al, 2020).
How stable is the supply of HQ to Alberta?
HQ is an oral tablet is offered by four manufacturers in Canada. Overall there is a commitment to ensure continued supply at historical rates to ensure continued access for patients on HQ for other conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis).
With the worldwide focus on HQ use in COVID-19, it is anticipated that supplies beyond historical use will be limited and inappropriate use will result in reduced access for patients with chronic rheumatologic conditions such as lupus and rheumatoid arthritis that require ongoing maintenance therapy.
While AHS can directly assess its current HQ stock, this is not possible for community pharmacies.
The evidence for these research questions is rapidly evolving. There are several clinical trials underway investigating the prophylactic and treatment effectiveness of HQ. This review will be updated as new data from additional trials is made available. It will be important to be able to assess the quality and outcomes of these upcoming human clinical trials to understand the efficacy of HQ in COVID-19.
Authorship & Committee Members
This review was updated by Jamie Boyd and scientifically reviewed by Mark Yarema (external reviewer), Braden Manns (co-chair), and Riley Hartmann (external reviewer). The full Scientific Advisory Group was involved in discussion and revision of the document: Lynora Saxinger (co- chair), John Conly, Alexander Doroshenko, Shelley Duggan, Nelson Lee, Elizabeth MacKay, Andrew McRae, Jeremy Slobodan, James Talbot, Brandie Walker, and Nathan Zelyas.
University of Huddersfield