Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management: based on information as at 20 May 2020

WHO REGIONAL OFFICE FOR AFRICA COVID-19 RAPID POLICY BRIEF SERIES SERIES 1: COVID-19 CASE MANAGEMENT- TREATMENT OPTIONS NUMBER: 001-01: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management Based on information as at 20 May 2020 Number: 001-01: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management WHO/AF/ARD/DAK/03/2020 © WHO Regional Office for Africa 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. 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Designed and printed in the WHO Regional Office for Africa, Brazzaville, Co ngo 1 RAPID POLICY BRIEF NUMBER: 001-01 RESEARCH DOMAIN: COVID-19 Case management- treatment options TITLE: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management RAPID POLICY BRIEF NUMBER: 001-01 1 RAPID POLICY BRIEF NUMBER: 001-01 2 RESEARCH DOMAIN: COVID-19 Case management - treatment options 3 TITLE: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management 4 DATE OF PUBLICATION: 26/05/2020 5 BACKGROUND The pandemic coronavirus disease-19 (COVID-19) has pushed the global healthcare system to a crisis with socioeconomic consequences negatively affecting all areas of activities around the world. While researches are underway to confirm an approved treatment, several treatment protocols are in use and are diversely appreciated. Among these drugs, antimalarial drug chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have been suggested as a treatment [1]. This policy brief aims to summarize views from the scientific community regarding the use of CQ/HCQ for COVID-19 treatment. 6 SEARCH STRATEGY / RESEARCH METHODS The research methodology consisted in using three databases: PUBMED, WHO COVID-19 and IRIS (WHO Institutional Repository for Information Sharing) to pull out papers published from January to 20 May 2020. The search terms used in that approach were: “chloroquine (CQ)”, “hydroxychloroquine (HCQ)”, “COVID-19 treatment”, “coronavirus disease-19”, “COVID-19 prophylaxis”, “chloroquine effectiveness”, and “COVID-19 case management”. First inventory was to explore papers on the subject and scoped Africa related evidences. With this search strategy, 81 titles and abstracts of studies published in English were found. Further screening of the abstracts, 13 publications were retained according to the inclusion criteria. Full texts of these publications were requested and used for this summary. 7 SUMMARY OF GLOBALLY PUBLISHED LITERATURE RELATED TO THE SUBJECT According to Katelyn et al. (qtd. in Tonnesmann et al), Chloroquine was first synthesized in 1934 and has been prescribed extensively for the prevention and treatment of malaria as well as the treatment of autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus [2, 3]. Hydroxychloroquine was later introduced in 1955 and quickly became favoured due to its superior safety profile [2]. Chloroquine and its derivatives, including the less toxic hydroxychloroquine, have been used to treat a variety of diseases including systemic lupus erythematous, rheumatoid arthritis and malaria, among many other indications. A big number of published papers reported effectiveness of CQ/CQH in the past decades in the malaria treatment. However Chloroquine resistance to p.falciparum malaria was documented in many countries including the African Region, although p. vivax remain sensitive to chloroquine in South East Asia and some other parts of the world. The discovery and development of artemisinin derivatives in 2 RAPID POLICY BRIEF NUMBER: 001-01 RESEARCH DOMAIN: COVID-19 Case management- treatment options TITLE: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management RAPID POLICY BRIEF NUMBER: 001-01 China, and their evaluation in South East Asia and other regions provided a new class of highly effective antimalarials. Artemisinin-based combination therapies (ACTs) are considered as the best current treatment for uncomplicated falciparum malaria compared to use of chloroquine and hence the WHO recommendation to countries based on the available evidence to change from the use of chloroquine to ACTs’[4]. Most countries in the WHO African Region changed their malaria treatment policy for P. falciparum between 1996 to 2004, first to SP or Amodiaquine as interim before ACTs; Choloroquine is however still being used for treatment of P. v in Ethiopia. With regards to CQ/HCQ’s effect on virus, there is common agreement on their effectiveness in vitro. All evidence suggests it is effective as an anti-viral agent when tested in cell cultures (in vitro) [1]. According to Beattie and Timothy (qtd. in Al-Bari), in-vitro studies have shown that chloroquine is effective against several viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV). Multiple mechanisms of action have been identified for chloroquine that disrupt the early stage of coronavirus replication. Moreover, chloroquine affects immune system activity by mediating an anti-inflammatory response, which might reduce damage due to the exaggerated inflammatory response [5, 6]. Success of CQ/HCQ for COVID-19 patients’ management is diversely appreciated by the scientific community. From January – April 2020, the paradoxical studies on the effect of CQ/HCQ on virus replication are of importance from a public health perspective. A French non-randomized open- label trial was conducted showing significant decrease in viral load and carriage duration in COVID- 19 patients receiving hydroxychloroquine (600 mg/day for ten days) with enhanced effects in combination with azithromycin [Mégarbane (qtd. in Gautret et al.) 7, 8]. Along the same line, the potential of HCQ in the treatment of 22 COVID-19 patients has been partially confirmed and considering that there is no better option at present, it is a promising practice to apply HCQ to COVID-19 under reasonable management [9]. However, Molina et al. founded no evidence of a strong antiviral activity or clinical benefit of the combination of hydroxy-chloroquine and azithromycin for the treatment of our hospitalised patients with severe COVID-19 [10]. A small randomized study from China reveals that in patients with mild to moderate COVID-19 found no difference in recovery rates after a use of HCQ [11]. After a review of studies conducted in different contexts and using various methodologies, there are no studies of CQ/HCQ as treatment of COVID- 19 that are adequately demonstrate efficacy or the absence of harm [2]. The efficacy and safety of CQ/HCQ for the treatment of COVID-19 remains to be defined [12]. To date, the epistemological robustness of different studies with regards to their methodologies and sample sizes does not allow for scientific unanimity on their findings. Research on the use of CQ/HCQ to care COVID-19 patients in the African region is still very weak and patchy. Most of the studies conducted to date on the subject are unanimously pointed to the need for continuing research by setting up randomized studies with samples that are statistically representative enough to facilitate decision-making based on evidence that is scientifically acceptable to all. 3 RAPID POLICY BRIEF NUMBER: 001-01 RESEARCH DOMAIN: COVID-19 Case management- treatment options TITLE: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management RAPID POLICY BRIEF NUMBER: 001-01 8 SUMMARY OF AFRICA-SPECIFIC LITERATURE ON THE SUBJECT Apart from anecdotal prophylactic use in management of COVID-19 patients in some countries and the study published by Abena et al calling African countries to strongly consider implementing prescription monitoring schemes to ensure that any off-label CQ/HCQ use is appropriate and beneficial during this pandemic [12, 13], there are no significant known Africa-specific studies. In addition, no adverse effects have been reported in grey, or published literature 9 POLICY FINDINGS The information currently is mixed. Supportive of its use is the long history of chloroquine efficacy in other similar coronaviruses, and use in the African region for malaria management – albeit at different dosages proposed for COVID-19 use. Additionally, it is comparatively inexpensive. On the other hand, the current scientific evidence is not conclusive on the usefulness, and side effects of hydroxychloroquine at recommended doses for its use in the management of COVID-19. Decisions about its use in countries should be taken with this guidance. 10 ONGOING RESEARCH IN THE AFRICAN REGION The use of hydroxychloroquine was being explored as part of the WHO solidarity trial that involves patients from multiple countries – see more information here: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel- coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. 11 AFRO RECOMMENDATIONS FOR FURTHER RESEARCH WHO AFRO encourages researchers to scientifically document the effectiveness of various CH/HCQ-based treatment protocols in the African region to provide scientific evidence to guide policies for the best management of COVID-19 patients. To this end, it invites all COVID-19 response committees to make optimal use of their scientific committees and extend collaboration to academics and other related partners to be able and undertake robust scientific studies on the subject. 4 RAPID POLICY BRIEF NUMBER: 001-01 RESEARCH DOMAIN: COVID-19 Case management- treatment options TITLE: Effectiveness of use of chloroquine/ hydroxychloroquine in COVID-19 case management RAPID POLICY BRIEF NUMBER: 001-01 12 REFERENCES [1] Sharma A. Chloroquine paradox may cause more damage than help fight COVID-19, Microbes and Infection, https://doi.org/10.1016/j.micinf.2020.04.004 [2] Katelyn A. Pastick, Elizabeth C. Okafor et al., Hydroxychloroquine and Chloroquine for Treatment of SARS- CoV-2 (COVID-19), Open Forum Infectious Diseases, 2020 [3] Tonnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy – a review of the literature. Immunopharmacol Immunotoxicol 2013; 35:434–42 [4] WHO Malaria Treatment Guidelines 2006 [5] Beattie RH Sturrock and Timothy JT Chevassut, Chloroquine and COVID-19 – a potential game changer? Clinical Medicine 2020 Vol 20, No3: 2 78–81 [6] MAA Al-Bari. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015;70:1608–21. [7] Mégarbane Bruno (2020): Chloroquine and hydroxychloroquine to treat COVID-19: between hope and caution, Clinical Toxicology, DOI: 10.1080/15563650.2020.1748194 [8] Gautret P, Lagiera 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 Agents. 2020 DOI: 10.1016/j.ijantimicag.2020.105949 [9] Zhaowei Chen, Jijia Hu, Zongwei Zhang, Shan Jiang, Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu and Zhan Zha. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial, medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758. [10] Molina J.M, Delaugerre C, LeGoff J, Mela-LimaB, PonscarmeD, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020 Mar 30. In press, pii: S0399-077X (20)30085-8.2 [11] Jinoos Yazdany and Alfred H.J. Kim. Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know. Ann Intern Med. doi:10.7326/M20-1334 [12] Abena Pascale M., Decloedt Eric H., Bottieau Emmanuel, Suleman Fatima, Adejumo Prisca, Sam-Agudu Nadia A., Muyembe TamFum Jean-Jacques, Seydi Moussa, Eholie Serge P., Mills Edward J., Kallay Oscar, Zumla Alimuddin, and Nachega Jean B. Chloroquine and Hydroxychloroquine for the Prevention or Treatment of Novel Coronavirus Disease (COVID-19) in Africa: Caution for Inappropriate Off-Label Use in Healthcare Setting, Am. J. Trop. Med. Hyg., 00(0), 2020, pp. 1–5 doi:10.4269/ajtmh.20-0290 [13] Elsevier. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19, International Journal of Antimicrobial Agents 55 (2020) 105932, www.elsevier.com/locate/ijantimicag BRIEF PRODUCED BY: Kwami Dadji, Humphrey Karamagi, Regina Titi-Ofei, Jean Claude Nshimirimana, Aminata B. Seydi, Pascal Mouhouelo, James Asamani, Hillary Kipruto, Julie Nabyonga, Akpaka Kalu and Felicitas Zawaira.