Re: Chloroquine and hydroxychloroquine in covid-19
Chloroquine and hydoxychloroquine in covid-19 infection
Whilst applauding Ferner and Aronson’s caution with regard to the use of chloroquine and hydoxychloroquine (HCQ) in covid-19 infection1 we feel that it is important to take exception with their conclusions that COVID-19 is untreatable and the title stating that The use of chloroquine and hydoxychloroquine is premature.
We need to declare that we wholeheartedly support recruitment of ongoing prospective large randomized controlled trials (RCTs) currently running in the UK (RECOVERY)2, in Europe (DISCOVERY)3 and worldwide (Solidarity)4. These trials will probably provide answers about the efficacy of anti-viral drugs, anti-inflammatory drugs, HCQ and Azithromycin (AZM) in COVID-19 patients.
However, we also recognise that the conclusion of these trials will take at least a few months while over 100,000 patients suffer from the disease worldwide and many thousands die from it on a daily basis.
In the meanwhile, several observational and uncontrolled studies have been published reporting that agents such as HCQ alone or HCQ with azithromycin (AZM) are helpful in the early stage of the disease by preventing disease progression and reducing viral transmission 5,6. Another study found that Remdesivir (an anti-viral agent used in Ebola) given on compassionate grounds was helpful in a more advanced stage of COVID-19 lung disease5 (also dubbed as cytokine storm phase) 7.
We, and indeed the authors of these studies, recognise their studies limitations and have advocated RCTs. HCQ and Remdesivir are included in the aforementioned trials.
We believe that, in the era of pandemic, these observational trials suggest that medications would justify off-label administration according to agreed protocols, until the results of trials are available. We do not advocate the universal prescription.
To take HCQ as an example. HCQ is an anti-microbial drug used in malaria. It is also an anti-inflammatory agent provided to patients with auto-immune diseases. Its in vitro anti-viral capability has been outlined in the editorial by Ferner and Aronson. These three properties coupled with the observational results would justify permitting the use of this drug in COVID-19 patients.
Ferner and Aronson have given contrary reasons (quoted by others in many arenas) for not using HCQ. We outline those reasons and our concerns regarding them.
The first reason is that HCQ is ‘toxic’ and ‘harmful’. Whilst HCQ has side effects, we believe that the toxicity profile has been exaggerated. The prolongation of QT interval and the ophthalmic toxicity are recognised, predictable, reversible and easy to monitor. These side effects are probably dose-related and appear more frequently with prolonged use. HCQ in COVID-19 is suggested to be used for up to 28 days and by most authors for 10-14 days.
Another excuse for not giving HCQ is the risk of depleting the market, thus depriving patients with systematic lupus erythematosus (SLE) and rheumatoid arthritis from obtaining the drug. This unfortunate excuse is voiced in western countries and not Asia or the middle east where pharmaceutical companies have increased production of HCQ.
A third excuse is that widespread use of these drugs will impair the results of the trials. Given the fact that most COVID-a19 patients are not part of clinical trials, providing HCQ, AZM or other antiviral treatments as adjudged by clinicians should not adversely influence running of clinical trials.
A fourth reason given not to prescribe HCQ was that many other agents were shown to be effective in vitro but did not show the same efficacy in patients. This is true but applying this on an off-label prescription of HCQ in not relevant as RCTs are likely to answer the question of efficacy.
The UK Chief Medical Officer has stipulated that HCQ is not licensed in COVID-19 outside clinical trials8. This position is in variance to the position of the European Medicine Agency9 and the US Food and Drug administration10 that allowed the use of off-label HCQ according to strict protocols. More recently the Australian government waived approval restrictions on using HCQ, Remdesivir, ritonavir and lopinavir 11.
Cortegiani et al. (Journal of Critical care) support the use of HCQ stating that the administration of the drugs “should adhere to the MEURI framework or after ethical approval as a trial as stated by the WHO. Data from high-quality, coordinated, clinical trials coming from different locations worldwide are urgently needed.” 12
With a 50% mortality rate for covid-19 patients entering ITU and 80% when put on a ventilator the off-label use of HCQ, AZM, anti-Il6 and antiviral agentes ahead of trials conclusion needs to be considered. As clinicians, we observe the course of the disease on our patients some of whom do not improve and die while being prohibited from prescribing inexpensive and relatively safe agents. We see it illogical that we are unable to prescribe HCQ and anti-viral agents while at the same time drugs which are not ‘licensed’ for COVID-19 and have no evidence behind them such as third generation cephalosporin can be freely administered.
The sickest patients are unlikely to respond to the drugs suggested above due to the lung cytokine storm occurring in the pre-death scenario. We would thus suggest that they are used carefully in patients before they reach the point that they need to be admitted to ITU. The Italian experience has confirmed that at the O2 ventilator stage the IL-6 anti-bodies used for Rheumatoid Arthritis are the only pharmaceuticals that make a difference 13 although we suspect Acyclovir may still help if reactivated CMV is fueling this scenario.
UK political and health officials including the Chief Medical Officer have been widely blamed for the delay in introducing various health and social measures in COVID-19. We would suggest that the restriction on prescribing HCQ and other agents should be relaxed in the UK so that, if trials proved its efficacy, this restriction will not be regarded as yet another delay.
A doctor’s duty is not to cause harm by intervention or by inaction. We do not see any conflict between enrolling patients in clinical trials and trying off-label HCQ, AZM, anti-viral drugs or anti-inflammatory agents in COVID patients according to logical protocols that include monitoring patients.
This, in our view, does not represent a disregard of the science of randomized controlled trials nor will it affect the recruitment to ongoing clinical trials. We see it as an extrapolation of practices from one disease to another, something that doctors successfully do all the time for the benefit of patients.
Paul R Goddard BSc (Pharmacology), MD, FRCR
Emeritus Professor, University of the West of England
Dr Nabil Jarad PhD FRCP
Consultant General and Respiratory Physician, Gloucestershire Hospitals, UK
Angus Dalgleish MD, FRCP, FMedSci
Professor of Immuno-Oncology, St Georges Hospital, London
1. Robin E Ferner, Jeffery K Aronson. Chloroquine and hydroxychloroquine in covid-19 BMJ 2020;369:1432
2. RECOVERY Trial. https://www.recoverytrial.net/
3. DISCOVERY trial. https://clinicaltrials.gov/ct2/show/NCT04315948.
4. Solidarity trial. Novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. https://www.who.int/emergencies/diseases/
5. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents2020:105949.
6. Gautret P, Lagier JC , Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study.
7. Jonathan Grein, Norio Ohmagari, Daniel Shin, et al Compassionate Use of Remdesivir for Patients with Severe Covid-19. New Eng J Med 2020; DOI: 10.1056/NEJMoa2007016
8. Chloroquine and Hydroxychloroquine not licensed for coronavirus (COVID-19) treatment
9. COVID-19: chloroquine and hydroxychloroquine only to be used in clinical trials or emergency use programs. https://www.ema.europa.eu/en/news/covid-19-chloroquine-hydroxychloroquin...
10. US Food and Drug Administration. Emergency use authorization (EUA) of hydroxychloroquine sulphate https://www.fda.gov/media/136537/download.
11. Hydroxychloroquine: Australian government waives regulatory requirements for drug
12. Andrea Cortegiani et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19, Journal of Critical Care, https://doi.org/10.1016/j.jcrc.2020.03.005
13. Personal communication to AD. April 15th 2020.
Competing interests: No competing interests