President Donald Trump has ignited the debate about chloroquine use in COVID-19. The drug is related to quinine, originally made from cinchona bark and chloroquine was synthesized and first sold in Europe in 1934 by Bayer for malaria and amoebiasis. Quinine was a critical medicine during the second world war, sourced mostly from Java. It fell into acute shortage after Pearl Harbour, was the subject of many US public health speeches over the years and plays a substantial role in US history.
The mechanism of action of chloroquine is well known. Chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor and interleukin-6, which mediate the inflammatory complications of several viral diseases (Savarino, Boelaert et al. 2003). However, in addition, it has been shown to be effective against SARS CoV-coronavirus (Keyaerts, Vijgen et al. 2004) and during the following 10 years was extensively studied in vitro and in vivo. In 2014 it was identified as one of four potential repurposed drugs for treatment of MERS SARS-COV (de Wilde, Jochmans et al. 2014). The others were chlorpromazine, loperamide, and lopinavir. The challenge with respiratory antivirals is to use them at the appropriate time, as both in in vivo and in clinical settings they may not necessarily change the clinical course of established disease, even if they are effective in inhibiting viral load. It appears, in spite of its known potential use against coronavirus, that chloroquine’s use in patients was not described in the literature until the Chinese reported both positive in vitro activity against SARS-CoV-2 and "superior" treatment effect in 100 COVID-19 patients in 10 hospitals (Gao, Tian et al. 2020). Since then, the global press has been awash with stories about whether or not chloroquine has some utility in treating COVID-19 cases.
Let’s look at the clinical evidence so far
Clinical studies conducted in COVID-19 patients and reported in 2020 are summarised in Table 1. In France, a small non-randomised, case controlled study in 26 patients and 16 controls (Gautret, Lagier et al. 2020) suggested faster conversion of reverse transcription polymerase chain reaction (RT-PCR) from positive to negative at 6 days. . Two randomised trials comparing chloroquine to standard of care (SOC) have been conducted, one studying viral load in 31 patients (Chen Jun, Liu Danping et al. 2020), and the other in 62 patients (Chen, Hu et al. 2020), looking at the accepted regulatory endpoint of time to clinical response. The latter study in mild, hospitalised patients showed a decrease in symptomology of approximately one day and an apparent decrease in progression to severe disease, with no patients progressing in the chloroquine group and 4 patients progressing in the control group.
Cortegiani et al. (5 March 2020) have conducted a useful review of articles and potential clinical trials. The trials are mostly RCTs, many single centre. Comparative treatments include SOC, placebo, lopinavir/ritonavir and umifenovir (a broad-spectrum antiviral licensed in Russia). The trials include patients diagnosed with mild, moderate and severe COVID-19 (including patients with COVID-19 pneumonia, and critically ill patients).
In addition, the World Health Organisation (WHO) is setting up the SOLIDARITY trial, an open-label study which will evaluate 4 treatment options for COVID-19, chloroquine being one of them. The others are the experimental antiviral compound remdesivir, a combination of two HIV drugs, lopinavir and ritonavir, and that same combination plus interferon-beta. At the time of writing, this study had yet to start recruitment but has 70 countries signed up to join it (World Health Organisation. 2020). The WHO issued a warning that "Until there is sufficient evidence, WHO cautions against physicians and medical associations recommending or administering these unproven treatments to patients with COVID-19 or people self-medicating with them. WHO is concerned by reports of individuals self-medicating with chloroquine and causing themselves serious harm".
The RECOVERY trial in the UK in which hydroxychloroquine is one of the four study arms, has already recruited 1000 patients in UK hospitals.
Results from the SOLIDARITY and RECOVERY trials, as well from the many other global trials will hopefully shed more light on the potential use of the hydroxychloroquine to treat COVID 19 in the near future.
Where are we?
Chloroquine/hydroxychloroquine is well characterised scientifically and clinically. It is currently off patent, cheap and can be relatively easily manufactured. Its safety profile is well-known to clinicians and regulators, and chloroquine is relatively safe as a short-term treatment as anyone who has lived in the tropics, such as one of our authors, can attest to. However, there are well characterised risks for certain patients, which have been documented in prescribing information in all countries where the drug is available.
Regulatory Agencies’ Positions
Different Regulatory Agencies have responded differently to the conundrum of whether or not to endorse the use of chloroquine/hydroxychloroquine for the treatment of COVID-19. In some countries (China, Netherlands and Italy) chloroquine phosphate and hydroxychloroquine sulphate are currently recommended for treatment of COVID-19 patients (Cortegiani, Ingoglia et al. 2020).
The US FDA encourages the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of treatments in treating COVID-19. FDA have authorised Emergency Use Authorisation (EUA) to facilitate the availability of chloroquine phosphate and hydroxychloroquine sulphate during the COVID-19 pandemic to treat patients for whom a clinical trial is not available, or participation is not feasible (FDA 2020).
In the EU, there is some provision under Regulation (EC) No. 726/2004 for formal compassionate use (CU) programmes regarding medicines qualifying for authorisation under the centralised procedure and similar to the EUA in the US. However, this provision refers to local regulations through the Competent Authorities (Milsted and Currie 15 August 2017). Specifically, it should be noted that on 1 April 2020, EMA issued guidance on the use of chloroquine for national emergency programmes for the treatment of COVID-19 (European Medicines Agency: EMA/170590/2020 2020), and hence individual countries in the EU are allowed to apply local regulations for compassionate use. The challenge in the UK is that the only mechanism available is the ‘named patient’ route, where an individual physician has to request the unlicensed medicine for each individual patient; clearly not an easy mechanism in these challenging times. The current statement from the MHRA is: "Until we have clear, definitive evidence that these treatments [chloroquine/hydroxychloroquine] are safe and effective for the treatment of COVID-19, they should only be used for this purpose within a clinical trial" (Medicines and Healthcare products Regulatory Agency 2020). The RECOVERY trial studying chloroquine is sponsored by UK Research and Innovation (UKRI) and the Department of Health and Social Care. It should be noted that, on 26 February 2020, the UK’s Department of Health and Social Care also took action to preserve national stocks of chloroquine by preventing its export (GlobalData Healthcare 2020).
Other countries in Europe, for example France, have published CU protocols, and therefore may move more quickly to institute CU programmes than those, like the UK, which restricted availability of chloroquine/hydroxychloroquine to named patient or clinical trial access. Presumably Netherlands and Italy also have mechanisms for early access as chloroquine appears in their guidance for certain patients (Cortegiani et al, 2020). Use of chloroquine in the emergency setting in the UK may need to be addressed.
Pharmaceutical companies can institute CU programmes for branded medicines. This mechanism was used successfully by Glaxo SmithKline for IV zanamivir after the H1N1 outbreak of flu in 2011 and at the time of registration of the drug for severe complicated flu (2019)(Zanamivir EPAR). EMA has just published guidance on the compassionate use of remdesivir in COVID-19 patients after an application by Estonia, Greece, The Netherlands and Romania. The guidance provides conditions of use, distribution and safety monitoring and identifies patients targeted for the treatment with remdesivir (hospitalised adults with COVID-19 who require invasive mechanical ventilation) (European Medicines Agency: EMA/178637/2020 2020).
What could this mean for Low- and Middle-Income Countries?
How are countries with less robust healthcare systems reacting? On 20 March 2020, the Nigerian National Agency for Food and Drug Administration and Control (NAFDAC) approved the production of chloroquine for clinical trial in Nigeria. NAFDAC went further, contacting May & Baker to request that they manufacture a batch of chloroquine for the Nigerian market (Obayendo 2020).
In Ghana, on 1 April 2020, the Minister of Health stated, "Ghana is treating its coronavirus cases with hydroxychloroquine". He went further and directed the Ghana Food and Drugs Authority to allow the importation of active ingredients for the manufacturing of hydroxychloroquine to augment the stock (GhanaWeb 2020). Anecdotal reports suggest that in Ghana, hydroxychloroquine is being used early in all positive COVID-19 cases.
In balancing the potential benefits against the risks of using a drug with promising, but as yet unconfirmed, efficacy in COVID-19, perhaps we should consider the vast disparities amongst healthcare systems globally. We know that approximately 20% of COVID-19 patients have a more severe illness requiring hospitalisation and possible ventilation, but what if you live in a part of the world where these commodities are in short supply? Take Ghana, for example, which is a nation of approximately 30 million. According to a BBC Focus on Africa, 1 April 2020, the Ghana Minister of Information reported that Ghana had been able to increase free beds for COVID 19 patients to approximately 200, with 50 more expected. He did not elaborate on how many of these beds had ventilators (Nyabor 2020).
If there are few hospital beds and fewer ventilators, the most prudent strategy would be to treat early, with a drug that is both cheap and has a known safety profile whilst, in parallel, awaiting confirmation of its efficacy through the large scale RCTs.
In New Delhi, hydroxychloroquine is being administered to the front-line healthcare professionals prophylactically (ref: private correspondence). In the absence of enough personal protective equipment (PPE), this may be a useful pragmatic approach.
This brief report has compared and contrasted how different countries are responding to early clinical trial data with chloroquine/hydroxychloroquine. Although this is a global pandemic, clearly when it comes to the management of COVID-19, one size does not necessarily fit all. Chloroquine is one of the medications that has made a difference to the evolution of humans over the last four centuries; could it re-emerge as vital in yet another disease indication as a medication in the fight against COVID-19?
- Chen Jun, Liu Danping, Liu Li, Liu Ping, Xu Qingnian, Xia Lu, Ling Yun, Huang Dan, Song Shuli, Zhang Dandan, Qian Zhiping, Li Tao, Shen Yinzhong and L. Hongzhou (2020). "A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)." J Zhejiang Univ (Med Sci) 49(1): 0-0
- Chen, Z., J. Hu, Z. Zhang, S. Jiang, S. Han, D. Yan, R. Zhuang, B. Hu and Z. Zhang (2020). "Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial." medRxiv: 2020.2003.2022.20040758
- Cortegiani, A., G. Ingoglia, M. Ippolito, A. Giarratano and S. Einav (2020). "A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19." J Crit Care
- de Wilde, A. H., D. Jochmans, C. C. Posthuma, J. C. Zevenhoven-Dobbe, S. van Nieuwkoop, T. M. Bestebroer, B. G. van den Hoogen, J. Neyts and E. J. Snijder (2014). "Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture." Antimicrob Agents Chemother 58(8): 4875-4884
- European Medicines Agency: EMA/170590/2020 (2020). COVID-19: chloroquine and hydroxychloroquine only to be used in clinical trials or emergency use programmes. EMA
- European Medicines Agency: EMA/178637/2020 (2020). Summary on compassionate use Remdesivir Gilead International Nonproprietary Name: remdesivir Procedure No.EMEA/H/K/5622/CU. Human Medicines Division
- FDA. (2020). "Coronavirus (COVID-19) Update: FDA Continues to Facilitate Development of Treatments." Retrieved 09 April 2020, 2020, from https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-facilitate-development-treatments
- Gao, J., Z. Tian and X. Yang (2020). "Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies." Biosci Trends 14(1): 72-73
- Gautret, P., J. C. Lagier, P. Parola, V. T. Hoang, L. Meddeb, M. Mailhe, B. Doudier, J. Courjon, V. Giordanengo, V. E. Vieira, H. T. Dupont, S. Honore, P. Colson, E. Chabriere, B. La Scola, J. M. Rolain, P. Brouqui and D. Raoult (2020). "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial." Int J Antimicrob Agents: 105949
- GhanaWeb. (2020). "Coronavirus: Regional breakdown of 195 cases." Retrieved 09 April 2020, 2020, from https://www.ghanaweb.com/GhanaHomePage/NewsArchive/Coronavirus-Regional-breakdown-of-195-cases-910744
- GlobalData Healthcare. (2020, 13 March 2020). "UK bans parallel export and hoarding of three Covid-19 drugs." Retrieved 09 April 2020, 2020, from https://www.pharmaceutical-technology.com/comment/parallel-export-covid-19/
- Keyaerts, E., L. Vijgen, P. Maes, J. Neyts and M. Van Ranst (2004). "In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine." Biochem Biophys Res Commun 323(1): 264-268
- Medicines and Healthcare products Regulatory Agency. (2020, 25 March 2020). "Chloroquine and Hydroxychloroquine not licensed for coronavirus (COVID-19) treatment " Retrieved 09 April 2020, 2020, from https://www.gov.uk/government/news/chloroquine-and-hydroxychloroquine-not-licensed-for-coronavirus-covid-19-treatment?utm_source=e9b36c55-1a1f-4fb8-8215-bb1bf1f82cdd&utm_medium=email&utm_campaign=govuk-notifications&utm_content=immediate
- Milsted, B. and E. Currie (15 August 2017). "Challenges of Programmes for Provision of Unlicensed Medicines Outside Clinical Trials"
- Nyabor, J. (2020, 02 April 2020). "Kojo Oppong Nkrumah speaks to BBC on governments efforts in COVID19 fight." Retrieved 09 April 2020, 2020, from https://www.universnewsroom.com/news/video-kojo-oppong-nkrumah-speaks-to-bbc-on-governments-efforts-in-covid19-fight/
- Obayendo, T. (2020, 20 March 2020). "NAFDAC Approves Chloroquine Production for Clinical Trial." Retrieved 09 April 2020, 2020, from https://www.pharmanewsonline.com/nafdac-approves-chloroquine-production-for-clinical-trial/
- Organisation., W. H. (2020, March 27 2020). "“Solidarity” clinical trial for COVID-19 treatments " Retrieved 09 April 2020, from https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
- Savarino, A., J. R. Boelaert, A. Cassone, G. Majori and R. Cauda (2003). "Effects of chloroquine on viral infections: an old drug against today's diseases?" Lancet Infect Dis 3(11): 722-727