key: cord-0824868-gnw8adj5 authors: Shah, Sanket; Das, Saibal; Jain, Avinash; Misra, Durga Prasanna; Negi, Vir Singh title: A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease‐19 (COVID‐19) date: 2020-04-27 journal: Int J Rheum Dis DOI: 10.1111/1756-185x.13842 sha: 867f54bce4a75faebfae4daeed8bbaac10501ee2 doc_id: 824868 cord_uid: gnw8adj5 OBJECTIVE: The pandemic coronavirus disease‐19 (COVID‐19) has pushed the global healthcare system to a crisis and amounted to a huge economic burden. Different drugs for prophylaxis against COVID‐19 including chloroquine (CQ) or hydroxychloroquine (HCQ) have been tried. This study was performed to systematically review the role of CQ and HCQ in preventing the spread of COVID‐19. METHODS: PubMed, EMBASE, ClinicalTrials.gov, International Clinical Trials Registry Platform and Cochrane Library databases were searched for studies that evaluated the prophylactic role of CQ or HCQ on SARS‐CoV‐2 (pre‐clinical studies) or COVID‐19 (clinical studies) until 30 March 2020. The available literature was critically appraised. RESULTS: A total of 45 articles were screened and 5 (3 in vitro pre‐clinical studies and 2 clinical opinions) were included. The pre‐clinical studies showed the prophylactic effects of CQ and HCQ against SARS‐CoV‐2. On the other hand, the clinical opinions advocated the prophylactic use of CQ and HCQ against COVID‐19. However, no original clinical studies on the prophylactic role of CQ or HCQ on COVID‐19 were available. CONCLUSION: Although pre‐clinical results are promising, to date there is a dearth of evidence to support the efficacy of CQ or HCQ in preventing COVID‐19. Considering potential safety issues and the likelihood of imparting a false sense of security, prophylaxis with CQ or HCQ against COVID‐19 needs to be thoroughly evaluated in observational studies or high‐quality randomized controlled studies. In such a scenario, understanding the impact on the economy is beyond the confines of a medical expert. Another conundrum faced is a high secondary infection rate among high-risk healthcare workers annexing the already burdened healthcare system. 3 This would not only compound the impending shortage of healthcare facilities but would also mean more pervasive spread. Prevention is thus the best strategy to not only prevent more spread and deaths but also to unburden the healthcare system. However, there are challenges involved. Although methods like mitigation, quarantine, isolation, social distancing, and so on are being employed, these are not infallible. Contact tracing for the spread of infection from asymptomatic or mild undiagnosed cases, transition to community spread, and factors such as uncertainty regarding the survival of the virus in air or fomites are cumulatively adding to the mammoth task. 4 Hence, the focus has now been shifted toward evaluating and implementing other strategies like chemoprophylaxis and vaccination besides the continued use of the barrier system. Vaccine development will take time, between 12-18 months, as human trials are under way. There is a lot of speculation on chemoprophylaxis stemming from the available data on the use of some antimalarial drugs, such as chloroquine (CQ) and hydroxychloroquine (HCQ), which have been tried for the treatment of this disease. 5 The potential drug targets depend on the natural cycle of this virus. The virus depends on pH-dependent internalization and fusion with lysosomes. HCQ and CQ target this pathway by increasing the pH as they get concentrated into the lysosome and endosomes. This, in turn, affects viral replication and also helps in immune regulation and prevention of a cytokine storm as the antigen presentation is affected. But the challenge is the translational impact of in vitro models to in vivo ones. There are studies from China and other countries highlighting the use of antimalarial anthraquinones including mention of the same in the latest guidelines. 6, 7 Recent advice issued by a national body from a South-Asian country suggested the use of prophylactic HCQ at a dose of 400 mg twice daily, followed by once weekly, for healthcare workers managing patients with COVID-19 and close contacts of proven COVID-19 cases. 8 However, these studies and guidelines differ on the prophylactic use of these drugs causing further dilemma among healthcare professionals. Hence, we aimed to systematically review the literature on the role of CQ or HCQ in preventing the spread of COVID-19. We aimed to include all completed and published pre-clinical as well as clinical studies, without limitations, which evaluated the prophylactic role of CQ or HCQ on SARS-CoV-2 (pre-clinical studies) or COVID-19 (clinical studies). We also looked for commentaries, reviews, viewpoints, or opinions if original clinical studies were not available. Studies which evaluated the therapeutic effects of CQ or HCQ were excluded. used in various combinations were: "chloroquine", "hydroxychloroquine", "anthraquinone", "CQ", "HCQ", "coronavirus", "coronavirus disease", "coronavirus disease-19", "COVID-19", "severe acute respiratory syndrome", "SARS-CoV-2", "prophylaxis", and "preventive". These search terms were adapted for use with different bibliographic databases in combination with database-specific filters for studies, if available. The search strategy was used to obtain the titles and the abstracts of the relevant studies in English, and they were independently screened by 2 authors, who subsequently retrieved abstracts, and if necessary, the full text of articles to determine the suitability. Disagreement resolution was done with a third author. The systematic review protocol could not be pre-registered as the current pandemic is an ongoing public health emergency, thereby resulting in a paucity of time to permit pre-registration. The clinical opinions were critically appraised following the checklist of McArthur et al (2015). 9 The characteristics of the pre-clinical studies were also critically appraised. This was performed independently by 2 authors, and disagreement resolution was done with a third author. No assumptions or simplifications were made during the process. At total of 45 articles were screened and 3 in vitro pre-clinical stud- The first in vitro study pointing toward the role of CQ and HCQ as pre-exposure prophylaxis against COVID-19 was published as a research letter by Yao et al 10 Vero cell lines derived from African green monkey kidney were treated with CQ or HCQ before exposing to a clinically isolated novel coronavirus strain (C-Tan-nCoV Wuhan strain 01) at a multiplicity of infection (MOI) of 0.05. HCQ was more potent than CQ in achieving the 50% maximal effective concentration (EC 50 ) (6.25 and 5.85 μmol/L at 24 and 48 hours, respectively). The concentration to achieve EC 50 was >100 and 18.01 μmol/L for CQ, suggesting a higher loading dose. This study led to the enthusiasm of registration of clinical trials on the prophylactic role CQ and HCQ ( Table 3 ). The study also highlighted the use of a high loading dose of CQ followed by a low maintenance dose to support its pharmacokinetic property of higher cellular accumulation and prolonged elimination half-life. Another in vitro study by a different group of researchers from China compared HCQ to CQ at 4 different MOI. 11 The results were contradictory to that of the previous study showing a lower EC 50 of CQ than that of HCQ. Importantly the difference was even more striking at higher MOI, suggesting that in the presence of faster multiplication of the virus, CQ may perform better than HCQ. 18 Clinical trials of CQ as prophylaxis failed in influenza 19 despite strong in vitro efficacy. 18 Even in Chikungunya, the viral replication paradoxically enhanced in animal models after CQ administration. 20 In a clinical trial, long-term musculoskeletal symptoms were more frequent in patients treated with CQ as compared to placebo. 20 Another critical concern is the toxicity of these drugs. CQ has a narrow safety margin and may cause several cardiovascular adverse effects, including QT prolongation, as well other unforeseen adverse reactions. 21 HCQ is relatively safer. However, unrestricted acute overdosing of these drugs can lead to serious toxicities. Moreover, these adverse events may get augmented due to potential drug inhibitors like cytochrome P-450 system inhibitors, as well as with other drugs being advocated or evaluated in COVID-19 such as azithromycin 6 and protease inhibitors. 22, 23 In the absence of robust in vivo and clinical evidence, it seems premature to recommend CQ and HCQ as a panacea for prophylaxis of COVID-19. In the current COVID-19 pandemic, quarantine, social distancing, and personal hygiene seem the only proven preventive measures. 24 It is pertinent to mention here that from the regulatory The pandemic COVID-19 has pushed the global healthcare system to a crisis and amounted to a huge economic and societal burden. Prevention of transmission of the disease in the population, particularly among high-risk individuals, is the urgent need of the hour. date there is dearth of good-quality evidence to support the clinical efficacy of CQ or HCQ in preventing COVID-19. Because of the lack of robust clinical evidence to date and duly considering the questionable efficacy, safety concerns, danger of deprivation of these essential drugs to legitimate patients due to panic stocking and instilling a false sense of protection among the common masses, the prophylactic use of CQ or HCQ against COVID-19 needs to be further reviewed as more data pour in. The authors declare there is no conflict of interest associated with this manuscript. Real estimates of mortality following COVID-19 infection COVID-19: protecting health-care workers Presumed asymptomatic carrier transmission of COVID-19 Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment Advisory on the Use of Hydroxy-Chloroquine as Prophylaxis for SARS-CoV-2 Infection Innovations in the systematic review of text and opinion In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression Chloroquine for the 2019 novel coronavirus SARS-CoV-2 Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model Chloroquine administration does not prevent Nipah virus infection and disease in ferrets Chloroquine is effective against influenza A virus in vitro but not in vivo. Influenza Other Respir Viruses Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection Goodman & Gilman's: The Pharmacological Basis of Therapeutics A Trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19 Antimicrobials and QT prolongation Isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-nCoV) outbreak We are now Receiving Patients Suffering from Chloroquine Poisoning, Says Lagos Govt, NCDC Cautions Nigerians What's Spreading Faster than Coronavirus in the US? Racist Assaults and Ignorant Attacks Against Asians CNN While People Clapped for those in Front Line Fighting Virus, Telangana Landlords Leave Doctors Homeless A systematic review of the prophylactic role of chloroquine and hydroxychloroquine