key: cord-0733210-w1au4pyl authors: Rawaf, S.; Al-Saffar, M.; Quezada-Yamamoto, H.; Alshaikh, M.; Pelly, M.; Rawaf, D.; Dubois, E.; Majeed, A. title: Chloroquine and hydroxychloroquine effectiveness in human subjects during coronavirus: a systematic review date: 2020-05-11 journal: nan DOI: 10.1101/2020.05.07.20094326 sha: 1dc06b667e18ed178765b80f794ecfffa165e4cb doc_id: 733210 cord_uid: w1au4pyl In a search to find effective treatments for COVID-19, chloroquine and hydroxychloroquine have gained attention. We aim to provide evidence to support clinical decision-making regarding medication for the treatment of COVID-19 by carrying out a systematic review of the literature. The electronic databases MEDLINE, EMBASE, Global Health, and HMIC were searched up to April 2020. Eligible study outcomes included: extubation or patient recovery. Relevant data were extracted and analysed by narrative synthesis. Our results included six studies in the review of which four studies were of good or fair quality. All eligible studies included were for coronavirus involving the use of either chloroquine or hydroxychloroquine to treat common symptoms such as fever, cough, shortness of breath and fatigue. Outcomes most commonly reported were improved lung function, viral clearance, and hospital discharge. Strong evidence to support the use of chloroquine and hydroxychloroquine in the treatment of COVID-19 is lacking. Fast track trials are riddled with bias and may not conform to rigorous guidelines which may lead to inadequate data being reported. The use of these drugs in combination with other medications may be useful but without knowing which groups they are suited for and when they may cause more harm than good. As the COVID-19 pandemic has streaked around the plant, the pursuit for therapeutic options has developed at a fast pace. Coronaviruses are not new. In the past two decades, the virus was responsible for previous outbreaks of Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS). Yet despite this experience, no clear treatment pathway had been agreed in some countries. Therefore, this current pandemic of a variant novel virus has taken the world by surprise with the only option of delivering empirical treatment at the early stages, until a vaccine is available. In a search to find effective treatments for COVID-19, chloroquine (CQ) and hydroxychloroquine have entered the spotlight (1). Current evidence comes from poorly controlled clinical trials demonstrating antiviral activity against severe-acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2). Systematic reviews of variable quality have started to appear focusing on current patients without looking at past evidence with other viruses of the same family (3) . To date, no systematic reviews have been published examining the clinical effectiveness of chloroquine and hydroxychloroquine in the context of the current pandemic or of past treatment for patients with severe coronavirus respiratory infections. Past outbreaks of coronaviruses have documented some useful treatments including chloroquine and hydroxychloroquine. These compounds are used to treat malaria, systemic lupus erythematosus and other rheumatic diseases. Chloroquine increases endosomal pH required for virus/cell fusion and interferes with the glycosylation of cellular receptors of SARS-CoV (4). Authors Wang et al. (5) reported that chloroquine . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . https://doi.org/10.1101/2020.05.07.20094326 doi: medRxiv preprint functions at both entry and post-entry stages of the 2019-nCoV and in addition to its antiviral activity, has an immune-modulating effect (5) . The 90% effective concentration (EC90) value of chloroquine against the 2019-nCoV in vitro, was demonstrated to be clinically achievable in the plasma of rheumatoid arthritis patients who received 500 mg (6) . The metabolism of chloroquine after oral administration occurs mostly in the liver. Its excretion is slow and maintains a plasma half-life of 2.5 to 10 days. Furthermore, individuals with impaired or compromised liver function at baseline (e.g. ventilated patients in ITU with multiple fat-soluble infusions running) are more likely to experience accumulation in-vivo and require close monitoring of liver function test and risk of liver failure. The adult acute lethal dose of chloroquine is between two to four grams in ages 18 to 65, according to the Wuhan Institute of Virology (7) . The study does not to stop at what medication is appropriate but also requires knowing when it is better to start treatment. From SARS we know that clinical worsening of individuals in Week 2 is apparently more related to immunopathological damage than to uncontrolled coronavirus replication (8). Keyaerts et al. (9) observed that chloroquine displayed significant anti-SARS-CoV activity (9) , but that inhibitory capability sharply declined if not administered within five-hour post infection (9) . Yet, advantages of chloroquine such as low cost and well-established safety could allow its use as prophylaxis in individuals at high risk such as healthcare workers (10) . The aim of this research is to report the existent clinical evidence of chloroquine and hydroxychloroquine effectiveness, either alone or in combination, in the recovery of human patients infected with coronavirus respiratory infections. In addition, difference in dosages and treatment initiation times will be analysed. Literature searches with medical electronic databases were conducted for studies published from 1950 onwards: Ovid MEDLINE, EMBASE, Global Health, and HMIC. Please refer to S1 file for an example of our search strategy. Studies on the use of chloroquine and hydroxychloroquine in treatment for coronavirus respiratory symptoms, on human patients (children or adults) diagnosed with SARS, MERS, COVID-19. Studies needed to include at least one of the following outcomes: elimination of active infection (detected in blood or swabs), recovery understood as no active infection or reduction of symptoms to an acceptable level for discharge or extubation from ventilators. Only studies with full text available in English were included. Studies conducted solely in healthy subjects or for the common cold were excluded, as were rapid reviews, narrative reviews, comments, opinion pieces, methodological reports, editorials, letters and conference abstracts. Non-human studies such as mice or in-vitro cultures were also excluded. The search included MeSH terms. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 11, 2020 Study selection was conducted by two reviewers independently. Title and abstract screening followed by full texts were performed using Covidence software against eligibility criteria. After deduplication, each reviewer summarised results and compared. Any disagreement was resolved by discussion. Discrepancies were resolved by consensus. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Please see S1 file: Table 4 ). Selected studies were exported, stored and tracked on the computer software reference manager Zotero. Data relevant to the study question were extracted from included studies and summarized. Information on author, study design, associated with the treatment of coronavirus using chloroquine or hydroxychloroquine was collected. The quality of the primary studies was assessed by three reviewers and scored using the National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools for controlled intervention studies, observational studies, and systematic reviews (11) . For quality assessment in case reports and case series, Murad et al. (12) tool was used. Studies were not excluded based on quality assessment. Studies were critically appraised for risk of bias. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 11, 2020 Outcomes such as extubation from ventilators or patient recovery. The latter defined as no active infection in either blood or swabs; or reduction of symptoms to an acceptable level for patient discharge from hospital. Due to methodological heterogeneity and varying clinical outcome measures reported across studies, a meta-analysis of results was not performed. A narrative synthesis of the finding was conducted. The search identified 575 papers, of which six studies met the eligibility criteria (Please see S2 file: Figure 1 ): two systematic reviews (13, 14) , one randomised control trial (15), one non-randomised clinical trial (16) , one an observational cohort study (17) , and one case report (18) . Study characteristics are summarised in Table 1 . The six selected studies were scored using the National Heart, Lung, and Blood Institute (NHLBI, Maryland, USA) and Murad et al quality assessment tools. Two scored poor (13, 16) ; two as good (14, 18) ; and two as fair (15,17) ( Table 1 ). The clinical study by Huang et al. (15) demonstrated that patients treated with chloroquine (500 mg orally, twice daily for 10 days) appear to show better patient recovery compared with those patients treated with lopinavir/ritonavir. As a result, the patients treated with chloroquine were discharged from hospital earlier. Table 1 summarises the results of eligible studies on the effectiveness of drugs in treating infected coronavirus patients. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . In the study by Gautret et al. (16) 70% of patients treated with 600 mg of hydroxychloroquine (200 mg, three times per day for 10 days) were virologically cured at day six post inclusion, compared to 12.5% of patients in the control group (p=0.001). In another group, 100% of Patients treated with hydroxychloroquine and azithromycin were virologically cured at day 6 post inclusion compared with 57.1% patients treated with hydroxychloroquine alone, and 12.5% in the control group (p<0.001). Gautret et al. (17) carried out a cohort study where they looked at the outcomes of patients treated with a combination of hydroxychloroquine sulfate (200 mg, three times per day for 10 days for four days) and antibiotic azithromycin (500 mg on day 1 followed by 250 mg per day for next four days), reporting positive results from the study. A broad-spectrum antibiotic (ceftriaxone) was added in those who developed pneumonia. The case report study by Spezzani et al. (18) reported that patients treated with darunavir/cobicistat and hydroxychloroquine (200 mg, twice daily) in combination with a triple antibiotic therapy (levofloxacin, piperacillin plus tazobactam) had a better outcome compared to darunavir/cobicistat and hydroxychloroquine combined with double therapy of ceftriaxone and azithromycin. Both Italian patients started treatment at admission, seven days after initial symptoms. Despite this, the couple achieved remission on different weeks as the course of the disease differed due to individual risk factors. Patient one had metastatic breast cancer and recent exposure to antineoplastic chemotherapy which had produced leukopenia (immunosuppression) at admission, whereas there was no hint of a significant immunosuppression of patient two. However, patient one had a rapid recovery compared to a prolonged and more severe course compared to patient two who had a relatively low risk profile except for hypertension. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . The systematic review by Singh et al. (13) looked at the effects of hydroxychloroquine and its impact on COVID-19 patients with type 2 diabetes in resource constrained settings with reference to India. They provide the current dosage guidelines on chloroquine and hydroxychloroquine use from China, South Korea, United States, Netherlands, Canada, and Belgium for the treatment of COVID-19 using chloroquine and hydroxychloroquine (13) . Dosage recommendations for adults from each of these sources vary depending on the severity of the cases. Based on the results of the study, the authors conclude that because of its limited side effects, availability, and costeffectiveness, the drugs should be worthy for fast track clinical trials for treatment of COVID-19. However, another systematic review by Sarma et al. (14) found that when compared to conventional treatment, there was no difference observed in virological cure, death, clinical worsening of disease, or safety. The main benefit was that treatment with hydroxychloroquine alone resulted in a lower number of cases showing radiological progression of lung disease. Additional benefits included less days to temperature normalisation and lowered total cough days compared to conventional treatment. The authors recommended that more data is acquired before making a definitive conclusion on the safety and effectiveness of the drugs. The results of this systematic review indicate a positive trend favouring the use of chloroquine singularly or the combination of hydroxychloroquine with antibiotic therapy (regardless of added bacterial infection at the beginning of the treatment). Evidence was insufficient to favour a treatment start on Week one versus Week two (or vice . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . versa) of symptoms appearing. However, Spezzani et al. (18) showed that immunosuppression may actually enhance treatment effectiveness by the use of the combination of hydroxychloroquine, antibiotic therapy and darunavir/cobicistat in patients who started treatment seven days after initial symptoms. These findings have implications for clinical practice and policy in the current pandemic. Despite the potential therapeutic effect of chloroquine and hydroxychloroquine, fears exist that excess demand may lead to a shortage for people with other diseases who are currently taking these drugs (19) . Chloroquine and hydroxychloroquine are usually safe and well tolerated in normal dosage but can be extremely toxic in overdose. Potential adverse effects that should be considered before prescribing include prolongation of the QT interval (especially in pre-existing cardiac disease or if combined with azithromycin), hypo-glycemia, neuropsychiatric effects, drug-drug interactions and idiosyncratic hypersensitivity reactions (20) . Moreover, chloroquine is not as widely available as hydroxychloroquine in some countries and is associated with greater adverse effects such as interaction with lopinavir/ritonavir, resulting in prolongation of the QT interval (21). To our knowledge, this systematic review is the first attempt to gather evidence from fully published studies that focus on the treatment, to date, of coronavirus outbreaks in human subjects. Contrasting to ours, previous research explores the suitability of either chloroquine or hydroxychloroquine in treating coronavirus by relying on findings from animal studies and dosage recommendations from unpublished trials. Our search identified six eligible studies. Two scored highly in the methodological quality assessment. This may be due to small sample size, unclear or absent . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. Two studies (15, 16) outline key information on socio-demographic and clinical characteristics; both used comparison groups to test the effectiveness of the drugs. Patients were tested before hospital admission and then prior to being administered the specific dosage of chloroquine and hydroxychloroquine. In both studies, patients were monitored and given treatment for 10 days with reported outcomes focused on viral clearance and lung improvement. Our review also included a case-report (18) identifying two patients from the same household discharged from hospital following combination therapy of antibiotics and hydroxychloroquine (18) . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . https://doi.org/10.1101/2020.05.07.20094326 doi: medRxiv preprint 13 systematic reviews and a case-report which met our inclusion criteria (13, 14, 18) . A summary of past and ongoing trials found across the included studies can be consulted in Table 2 . Recent public and media attention in many countries on the use chloroquine and hydroxychloroquine has increased focus on repurposing the drugs to combat the COVID-19 pandemic. This has prompted the World Health Organisation to reconsider leaving both drugs out from a large trial to study the effectiveness and safety of promising medications suitable for treating COVID-19 patients (24). Other institutions have also began launching fast track trials to understand whether they help in the recovery time and outcomes, but these types of studies come with issues of design bias which is unlikely to provide important data on the true effects of the drugs. Without essential data to provide key information about the suitability of these compounds in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . https://doi.org/10.1101/2020.05.07.20094326 doi: medRxiv preprint different populations, it will difficult to provide them to those who need them the most. Future research should adhere to the rigorous standard guidelines for the randomised control and observational cohort studies as best as possible, so that valuable and unbiased information is provided on these medications. The current evidence that exists on real human patients is weak despite effectiveness shown in in-vitro cultures for past coronavirus outbreaks and with the COVID-19 variant. It is unclear if there is an effect on the effectiveness, depending on early or late stage of administration. Nevertheless, recent clinical trials suggest a more positive outcome for those patients treated with chloroquine singularly or hydroxychloroquine combinations. Off-label use of these drugs for COVID-19 could raise the demand which would require a counterbalance in production. Otherwise, this may lead to a negative impact for those treated for malaria, lupus and other rheumatic diseases. Further randomised trials are needed urgently. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. None declared . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. The virological clearance day-6 post-inclusion (primary outcome) with HCQ vs. control was 70.0% versus 12.5%, respectively (p = 0.001). Note: a small sample size, dropout of six patients and limited follow-up, apart from the non-randomized and open-label nature of the trial. Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know. Annals of Internal Medicine Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19 Infection-A Systematic Literature Review. medRxiv Available from Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. The American Journal of Medicine Controversial treatments: An updated understanding of the coronavirus disease 2019 Effects of chloroquine on viral infections: an old drug against today's diseases. The Lancet Infectious Diseases In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochemical and Biophysical Research Communications Overview of antiviral and anti-inflammatory treatment for severe acute respiratory syndrome Study Quality Assessment Tools | National Heart, Lung, and Blood Institute (NHLBI) Methodological quality and synthesis of case series and case reports Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & Metabolic Syndrome Virological and Clinical Cure in Covid-19 Patients Treated with Hydroxychloroquine: A Systematic Review and Meta-Analysis Treating COVID-19 with Chloroquine Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Medicine and Infectious Disease Benign COVID-19 in an immunocompromised cancer patient -the case of a married couple Potential of chloroquine and hydroxychloroquine to treat COVID-19 causes fears of shortages among people with systemic lupus erythematosus Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine exp Coronavirus/ or Coronavirus.mp. or exp Coronavirus Infections or exp Middle East Respiratory Syndrome Coronavirus Middle East Respiratory Syndrome.mp exp SARS Virus/ or SARS.mp. or exp Severe Acute Respiratory Syndrome Severe Acute Respiratory Syndrome.mp exp Respiratory Distress Syndrome, Adult/ or ARDS.mp Acute Respiratory Distress Syndrome.mp Studies included were last searched on the 19th April 2020.The articles identified through the search included text words, in the following combination: 4 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). 10 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding