key: cord-327360-4qpk99x9 authors: Elsawah, Hozaifa Khalil; Elsokary, Mohamed Ahmed; Elrazzaz, Mahmoud Gamal; ElShafey, Ahmed Hane title: Hydroxychloroquine for treatment of non‐severe COVID‐19 patients; systematic review and meta‐analysis of controlled clinical trials date: 2020-08-18 journal: J Med Virol DOI: 10.1002/jmv.26442 sha: doc_id: 327360 cord_uid: 4qpk99x9 BACKGROUND: Being a pandemic and having a high global case fatality rate directed us to assess the evidence strength of hydroxychloroquine efficacy in treating COVID‐19 arising from clinical trials and to update the practice with the most reliable clinical evidence. METHODS: A comprehensive search was started in June up to July‐18, 2020 in many databases, including PubMed, Embase and others. Of 432 studies found, only six studies fulfilled the inclusion criteria which includes: clinical trials, age>12 years with non‐severe COVID‐19, PCR‐confirmed COVID‐19, hydroxychloroquine is the intervention beyond the usual care. Data extraction and bias risk assessment were done by two independent authors. Both fixed‐effect and random‐effect models were utilized for pooling data using risk difference as a summary measure. The primary outcomes are clinical and radiological COVID‐19 progression, SARS‐CoV‐2 clearance in the pharyngeal swab, and mortality. The secondary outcomes are the adverse effects of hydroxychloroquine. RESULTS: Among 609 COVID‐19 confirmed patients obtained from pooling 6 studies, 294 patients received Hydroxychloroquine and 315 patients served as a control. Hydroxychloroquine significantly prevent early radiological progression relative to control with risk difference and 95% confidence interval of ‐0.2 (‐0.36 to ‐0.03). On the other hand, hydroxychloroquine did not prevent clinical COVID‐19 progression, reduce 5‐days mortality, or enhance viral clearance on days 5, 6, 7. Moreover, many adverse effects were reported with hydroxychloroquine therapy. CONCLUSIONS: Failure of hydroxychloroquine to show viral clearance or clinical benefits with additional adverse effects outweigh its protective effect from radiological progression in non‐severe COVID‐19 patients. Benefit‐risk balance should guide hydroxychloroquine use in COVID‐19. This article is protected by copyright. All rights reserved. authorization was also issued for HCQ in March and revoked in June 2020 due to safety and efficacy concerns 15 . HCQ is a weak base 4-aminoquinoline, developed in 1946 as an antimalarial agent, which is a safer derivative than chloroquine 16 . The antiviral activity of HCQ against viral diseases such as HIV and severe acute respiratory syndrome studied many years ago 17 . It also showed in vitro activity against SARS CoV-2 by inhibiting viral entry through targeting early endosomes and endolysosomes 18 . Moreover, HCQ could modulate the immune response and reduce proinflammatory cytokines 19 which are important inducers of acute respiratory distress syndrome 20 . Few retrospective observational studies reported some benefits in treating COVID-19 patients, where HCQ decreased mortality and IL-6 level 21 , decreased case fatality rate 22 , and improved patient survival 23 . On the other hand, other observational studies reported no benefits and more frequent side effects while using HCQ [24] [25] [26] . The same controversies are found in the randomized clinical trials (RCT) that investigated HCQ efficacy in COVID-19. Additionally, HCQ is one of the most widely used agents for treating COVID-19 infection despite insufficient supporting evidence. A few numbers of meta-analyses investigating this subject were conducted. However, they were criticized for some flaws addressed and discussed afterward. Therefore, there is an urgency to conduct a systematic review and meta-analysis including all available clinical trials that meet the prespecified inclusion criteria. The objectives are to summarize efficacy of HCQ use in COVID-19 relative to control based on available clinical trials indicated by all possible improvements of the disease This article is protected by copyright. All rights reserved. and to pool all short-term possible side effects related to HCQ therapy in COVID-19 patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement were followed to improve reporting the present systematic review 27 . The protocol was registered in the international prospective reregister of systematic review (PROSPERO) with registration number CRD42020195886 in June 2020. The inclusion criteria for the eligible studies for systematic review AND metaanalysis include: -Clinical trials either randomized or not -COVID-19 patients > 12 years -Infected with SARS CoV-2 and had a PCR confirmation test; the test should be based on nasopharyngeal or oropharyngeal swab. -Non-severe infection (mild and moderate) based on clinical assessment by each study. -The treatment arm is HCQ ± usual treatment that was given according to each hospital and was not proven to be anti-COVID-19. This article is protected by copyright. All rights reserved. -Control group is only on the usual treatment -Outcomes: any clinical outcomes or drug-related side effects during the follow-up period. The following databases were used for studies identification: PubMed, Embase, Cochrane, Google Scholar, ClinicalTrial.gov, ProQuest, Science direct, Chinese Clinical Trial Registry (ChiCTR) and medRxiv. The search started in June and continued through July 2020 to track all new studies. The advanced search was used in different databases with limitation to clinical trials and fields of title and abstract without other limitations. The synonyms applied in search terms were SARS or COVID and hydroxychloroquine or HCQ or Plaquenil. Three researchers independently underwent comprehensive searching and identified certain studies after removing duplicated ones. According to the PRISMA flow diagram (figure 1) 28 , the selection of eligible studies for meta-analysis from identified ones was conducted by two researchers through three steps; abstracts screening for relevant studies, full-text articles assessment for eligibility, and effect measures assessment for quantitative synthesis. Disagreements were resolved by discussion among the authors. This article is protected by copyright. All rights reserved. 2.6. Data collection process: "Data collection form for intervention reviews: RCTs and non-RCTs" developed by Cochrane was used for data extraction 29 . Numbers were extracted directly from text and tables and indirectly from graphs using Getdata graph digitizer version 2.26.0.20 30 . Data extraction was done by three independent authors. There are three types of variables; 1) independent variable is HCQ therapy, 2) dependent variables include viral clearance in the pharyngeal swab, clinical progression (increase in the baseline severity), radiological progression, adverse effects, and mortality, 3) confounders include usual treatment that varied among studies, age, sex, disease onset, and different HCQ doses. The Cochrane Risk of Bias Tools to assess the bias risk were followed 31 . It includes 6 domains: selection bias, reporting bias, performance bias, detection bias, attrition bias, and other sources of bias. The Consolidated Standards of Reporting Trials (CONSORT) were also utilized 32 . The risk of bias was assessed by three authors and a final consensus was done. Publication bias couldn't be assessed because of the low number of the included studies. Sensitivity analysis was performed after removing the low-quality studies. The principal summary measures were risk difference (RD) for the outcomes, odds ratio (OR) for gender, and mean difference (MD) for age with 95% confidence This article is protected by copyright. All rights reserved. interval (CI) to compare between HCQ arm and control arm using RevMan version 5.4. Statistical heterogeneity was tested using the Q statistic and quantified with I 2 value. Each of fixed-effect and random effect models was used to pool the effect sizes according to the heterogeneity of each outcome 33 . Mantel Hazel method and inverse variance method were used for dichotomous data and continuous data respectively. All-time point meta-analysis was used to summarize the result of viral clearance at each available time point. PRISMA flow diagram in figure (1) shows that 432 studies were identified after the removal of duplications, 391 studies were removed after screening titles and abstracts based on their relevance, and 36 studies were removed after assessment of full article for eligibility based on the inclusion criteria. The remaining 6 studies were included in the systematic review and meta-analysis. Some studies were excluded because of their retrospective design 34 , did not recruit PCR-confirmed cases 35, 36 , or recruited less than 12 years-old patients 36 . The population of the included studies had non-severe COVID-19 except 2 severe patients in Tang W. et al study 37 . The disease severity definition slightly varied by the studies. It was based on Chinese guidelines in three studies [37] [38] [39] [40] in Barbosa J. et al study 44 . The disease onset before HCQ treatment varied from 1 and 4 days in three studies [42] [43] [44] to 16 days in another study 37 . HCQ regimens varied among the studies; only three studies used loading doses of 800 and 1200 mg/d 37, 42, 44 . Maintenance daily doses of 200, 400, 600, 800 mg were also used according to each study (Table 1) . Usual treatment was given to all patients according to needs and varied widely among the studies. It included: supportive care, symptomatic treatment, steroids, antibiotics, and antivirals 37-39, 42, 43 (Table 1 ). The two groups were comparable in all mentioned baseline factors in each included study. The risk of bias is summarized in figure (2) . The study design of Barbosa J. et al was included as it emulated clinical trial design and the recall bias was unlikely 44 Heterogeneity was not significant (χ 2 = 2.47, P = 0.48). (Figure 4) 6-Twenty-eight-days mortality was not statistically significant between the two groups. RD pooled from two studies 37, 42 using fixed-effect model was 0.00 (-0.01 to 0.01). Heterogeneity was not significant (χ 2 = 0.00, P = 1). (Figure 4 After excluding the two low-quality studies 44, 45 , the same analyses on the applicable outcomes were performed. No difference was observed between the two analyses on the progression, mortality and viral clearance. HCQ therapy in COVID 19 is still a matter of debate among healthcare providers 47 . It was introduced early in the pandemic based on early studies 48 This article is protected by copyright. All rights reserved. observational and interventional studies raised concerns about the safety of the drug and even prematurely terminated due to serious cardiac side effects 24, 49-51 . Sensitive indicators for a possible efficacy of anti-COVID-19 drugs should rely on the improvement in the disease clinical course and modification in possible causes of the related mortality. Radiological abnormalities of the lung could be a good measure of the drug efficacy. Lung abnormalities on chest CT in COVID-19 patients changed gradually from ground-glass opacities on the first days to an increase in the crazypaving pattern after one week, then became consolidated on day 10 and started to resolve after 2 weeks of the disease course 52 . Ability of a drug to prevent disease progression from mild/moderate to severe has been targeted as a reliable efficacy measure 53 . Accordingly, it could inhibit the pathophysiological pathways of the virus. The disease severity was defined by WHO as SpO2 < 94% on room air, including those who require any form of supplemental oxygen 54 . Viral clearance is of clinical importance as it correlated with the clinical and biochemical outcomes 55 , but may underestimate the immunomodulators effect including HCQ 12, 56 . On the other hand, low rates of mortality were reported among non-severe COVID-19, large number is required to get enough power to show a significant difference 57 . Mortality may not be a sensitive indicator among those with non-severe COVID-19. The present meta-analysis targeted non-severe COVID-19 patients to assess the efficacy and safety of HCQ based on the available evidence. In addition, the minimal age of the inclusion criteria was expanded to 12 years to add more studies. HCQ was used in the RECOVERY trial for infants more than 6 months without concerns 58 , but it could not be included in this review as it also had no PCR-based confirmation test. This article is protected by copyright. All rights reserved. The present study offers moderate-quality evidence built on five clinical trials and one quasi-trial. The meta-analysis investigated five measurable objective outcomes, two of them showed statistical significance; chest CT progression and incidence of some adverse drug effects. However, clinical progression, viral clearance at three time points, and 5-days mortality did not differ between the two groups. all time points meta-analysis to summarize the effect size on 5, 6, and 7-days was performed to get more accurate results 59 . The chest CT-based disease assessment was performed on days 0 and 6 to evaluate the disease progression in Chen Z. et al study 39 . It depended on pneumonia absorption on CT and weather it was absorbed by more or less 50%, it also depended on pneumonia absorption on CT in Chen J. et al study 38 . The clinical progression definition was consistent in three studies [37] [38] [39] Large RCT with sufficient power is required with longer follow-up period, it should report more sensitive outcomes stratified by the disease severity and based on the proposed mechanisms of action of HCQ to improve the clinical course of COVID-19. A lot of limitations faced the investigators due to conflicts between the included trials, high level of heterogeneity which is present among some studies methodologies and outcomes such as COVID-19 severity definitions and the background treatment. The This article is protected by copyright. All rights reserved. low number of studies with relatively small sample size and low quality is also another challenge. There are no tangible beneficial effects of adding HCQ to the treatment of patients suffering from non-severe PCR confirmed COVID-19 infection. Reducing the chest CT progression by HCQ was neither sufficient to reduce the early mortality nor promote the early clinical progression more than the usual therapy used. Its use was accompanied with a significant incidence of adverse effects without any effect on viral clearance. Funding: None The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in WHO declares COVID-19 a pandemic Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiology and molecular biology reviews Epidemiology, genetic recombination, and pathogenesis of coronaviruses Global Comparison of Influenza Type A and B with COVID-19: A Systematic Review and Meta-Analysis on Clinical, Laboratory, and Radiographic Findings. Laboratory, and Radiographic Findings Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero? Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review Remdesivir as a possible therapeutic option for the COVID-19. Travel medicine and infectious disease Remdesivir Receives Emergency Use Authorization for Severely Ill Patients with COVID-19 Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence Pharmacology of chloroquine and hydroxychloroquine. Hydroxychloroquine and Chloroquine retinopathy New insights into the antiviral effects of chloroquine. The Lancet infectious diseases Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell discovery Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort Cytokine balance in the lungs of patients with acute respiratory distress syndrome. American journal of respiratory and critical care medicine Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19. medRxiv Full-length title: Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel medicine and infectious disease Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 Observational study of hydroxychloroquine in hospitalized patients with Covid-19 Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Study flow diagrams in Cochrane systematic review updates: an adapted PRISMA flow diagram Data collection forms for intervention reviews: Rcts and non-RCTs. Version GetData Graph Digitizer version 2.24. Available at www getdatagraph-digitizer com The Cochrane Collaboration's tool for assessing risk of bias in randomised trials Improving the quality of reporting of randomized controlled trials: the CONSORT statement Cochrane handbook for systematic reviews of interventions No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial Empirical treatment with hydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up by telemedicine Covid-19: Hydroxychloroquine does not benefit hospitalised patients, UK trial finds Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19) Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention A minimal common outcome measure set for COVID-19 clinical research. The Lancet Infectious Diseases Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19: a quasi-randomized comparative study 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 Antimalarial drugs in the treatment of rheumatological diseases Hydroxychloroquine for COVID-19: A review and a debate based on available clinical trials/case studies Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin QT interval prolongation and torsade De pointes in patients with COVID-19 treated with Hydroxychloroquine/azithromycin. Heart rhythm Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study) Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. The Lancet Infectious Diseases COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance The correlation between viral clearance and biochemical outcomes of 94 COVID-19 infected discharged patients Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive care medicine RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials Meta-analysis of repeated measures study designs Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic review and meta-analysis Hydroxychloroquine in patients with COVID-19: A Systematic Review and meta-analysis Hydroxychloroquine Versus COVID-19: A Periodic Systematic Review and Meta-Analysis