The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study
Tarek Sulaiman, Abdulrhman Mohana, Laila Alawdah, Nagla Mahmoud, Mustafa Hassanein, Tariq Wani, Amel Alfaifi, Eissa Alenazi, Nashwa Radwan, Nasser Alkhalifah, Ehab Elkady, Manwer Alanazi, Mohammed Alqahtani, Khalid Abdullah, Yousif Yousif, Fouad Abogazalah, Fuad Awwad, Khaled Alabdulkareem, Fahad Alghofaili, Ahmad Aljedai, Hani Jokhdar, Fahad Alrabiah
doi:10.1101/2020.09.09.20184143
BACKGROUND: Currently, there is no proven effective therapy nor vaccine for the treatment of SARS-CoV-2. Evidence regarding the potential benefit of early administration of hydroxychloroquine (HCQ) therapy in symptomatic patients with Coronavirus Disease (COVID-19) is not clear.
METHODS: This observational prospective cohort study took place in 238 ambulatory fever clinics in Saudi Arabia, which followed the Ministry of Health (MOH) COVID-19 treatment guideline. This guideline included multiple treatment options for COVID-19 based on the best available evidence at the time, among which was Hydroxychloroquine (HCQ). Patients with confirmed COVD-19 (by reverse transcriptase polymerase chain reaction (PCR) test) who presented to these clinics with mild to moderate symptoms during the period from 5-26 June 2020 were included in this study. Our study looked at those who received HCQ-based therapy along with supportive care (SC) and compared them to patients who received SC alone. The primary outcome was hospital admission within 28-days of presentation. The secondary outcome was a composite of intensive care admission (ICU) and/or mortality during the followup period. Outcome data were assessed through a follow-up telephonic questionnaire at day 28 and were further verified with national hospitalisation and mortality registries. Multiple logistic regression model was used to control for prespecified confounders.
RESULTS: Of the 7,892 symptomatic PCR-confirmed COVID-19 patients who visited the ambulatory fever clinics during the study period, 5,541 had verified clinical outcomes at day 28 (1,817 patients in the HCQ group vs 3,724 in the SC group). At baseline, patients who received HCQ therapy were more likely to be males who did not have hypertension or chronic lung disease compared to the SC group. No major differences were noted regarding other comorbid conditions. All patients were presenting with active complaints; however, the HCQ groups had higher rates of symptoms compared to the SC group (fever: 84% vs 66.3, headache: 49.8 vs 37.4, cough: 44.5 vs 35.6, respectively). Early HCQ-based therapy was associated with a lower hospital admission within 28-days compared to SC alone (9.4% compared to 16.6%, RRR 43%, p-value <0.001). The composite outcome of ICU admission and/or mortality at 28days was also lower in the HCQ group compared to the SC (1.2% compared to 2.6%, RRR 54%, p-value 0.001). Adjusting for age, gender, and major comorbid conditions, a multivariate logistic regression model showed a decrease in the odds of hospitalisation in patients who received HCQ compared to SC alone (adjusted OR 0.57 [95% CI 0.47-0.69], p-value <0.001). The composite outcome of ICU admission and/or mortality was also lower for the HCQ group All rights reserved. No reuse allowed without permission. perpetuity.
References
Arshad, Kilgore, Chaudhry, Jacobsen, treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalised with COVID-19, International Journal of Infectious Diseases
Boelart, Piette, Sperber, The potential place of chloroquine in the treatment of HIV-1-infected patients, Journal of Clinical Virology
Carlucci, Ahuja, Petrilli, Rajagopalan, Jones et al., Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalised COVID-19 patients, medRxiv,
doi:10.1101/2020.05.02.20080036Castelnuovo, Costanzo, Antinori, Berselli, Blandi et al., Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study, European Journal of Internal Medicine
Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19, New England Journal of Medicine,
doi:10.1056/NEJMoa2019014Chen, Hu, Zhang, Jiang, Han et al., Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomised clinical trial. medRxiv, Available online
Derwand, Scholz, Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19?, Medical Hypotheses,
doi:10.1016/j.mehy.2020.109815Fesen, Kohn, Leteurtre, Inhibitors of human immunodeficiency virus integrase, Proc Natl Acad Sci
Frisk-Holmberg, Bergqvist, Englund, Chloroquine intoxication, Br. J. Clin. Pharm
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomised clinical trial, International Journal of Antimicrobial Agents
Geleris, Sun, Platt, Zucker, Baldwin et al., Observational study of hydroxychloroquine in hospitalised patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2012410Guérin, Lévy, Thomas, Lardenois, Lacrosse et al., Azithromycin and hydroxychloroquine accelerate recovery of outpatients with mild/moderate COVID-19,
doi:10.20944/preprints202005.0486.v1Ip, Ahn, Zhou, Goy, Hansen et al., Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: A multi-center observational study, medRxiv,
doi:10.1101/2020.08.20.20178772Ip, Berry, Hansen, Goy, Pecora et al., Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients-An Observational Study,
doi:10.1101/2020.05.21.20109207Lagier, Million, Gautret, Colson, Sé et al., Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis, Travel Medicine andInfectiousDisease2020,
doi:10.1016/j.tmaid.2020.101791Li, Wang, Agostinis, Rabson, Melino et al., Is hydroxychloroquine beneficial for COVID-19 patients?, Cell death & disease
Mackenzie, Scherbel, Chloroquine and hydroxychloroquine in rheumatological therapy, Clin Rheum Dis
Mitjà, Corbacho-Monné, Ubals, Tebe, Peñafiel et al., Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomisedcontrolled trial, Clin Infect Dis,
doi:10.1093/cid/ciaa10092020Jul16Rosenberg, Dufort, Udo, Wilberschied, Kumar et al., Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state, JAMA,
doi:10.1001/jama.2020.8630Rynes, Ophthalmologic considerations in using antimalarials in the United States, Lupus
Savarino, Gennero, Sperber, The anti-HIV activity of chloroquine, Journal of Clinical Virology
Scholz, Derwand, Zelenko, COVID-19 Outpatients -Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study, Preprints,
doi:10.20944/preprints202007.0025.v1Stein, Gowda, Lifson, pH-independent HIV entry into CD4-positive cells via virus envelope fusion to the plasma membrane, Cell
Tang, Cao, Han, Wang, Chen et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ,
doi:10.1136/bmj.m1849Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell research
Worldometers, Info, Corona Virus: Saudi Arabia
Wu, Wu, Liu, Yang, The SARS-CoV-2 outbreak: what we know, International Journal of Infectious Diseases
Zhou, Zhang, Qu, Coronavirus disease 2019 (COVID-19): a clinical update, Frontiers of medicine
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'abstract': '<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>BACKGROUND</jats:title><jats:p>Currently, '
'there is no proven effective therapy nor vaccine for the treatment of SARS-CoV-2. Evidence '
'regarding the potential benefit of early administration of hydroxychloroquine (HCQ) therapy '
'in symptomatic patients with Coronavirus Disease (COVID-19) is not '
'clear.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>This '
'observational prospective cohort study took place in 238 ambulatory fever clinics in Saudi '
'Arabia, which followed the Ministry of Health (MOH) COVID-19 treatment guideline. This '
'guideline included multiple treatment options for COVID-19 based on the best available '
'evidence at the time, among which was Hydroxychloroquine (HCQ). Patients with confirmed '
'COVD-19 (by reverse transcriptase polymerase chain reaction (PCR) test) who presented to '
'these clinics with mild to moderate symptoms during the period from 5-26 June 2020 were '
'included in this study. Our study looked at those who received HCQ-based therapy along with '
'supportive care (SC) and compared them to patients who received SC alone. The primary outcome '
'was hospital admission within 28-days of presentation. The secondary outcome was a composite '
'of intensive care admission (ICU) and/or mortality during the follow-up period. Outcome data '
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'verified with national hospitalisation and mortality registries. Multiple logistic regression '
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'confounders.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Of the '
'7,892 symptomatic PCR-confirmed COVID-19 patients who visited the ambulatory fever clinics '
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'the HCQ group vs 3,724 in the SC group). At baseline, patients who received HCQ therapy were '
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'controlling for potential confounders (adjusted OR 0.55 [95% CI '
'0.34-0.91],<jats:italic>p-value</jats:italic>0.019).</jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p>Early '
'intervention with HCQ-based therapy in patients with mild to moderate symptoms at '
'presentation is associated with lower adverse clinical outcomes among COVID-19 patients, '
'including hospital admissions, ICU admission, and/or death.</jats:p></jats:sec>',
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'volume': '15',
'year': '1983',
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'2020 Version 1.6 May 24th.'},
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'https://www.worldometers.info/coronavirus/country/saudi-arabia/ '
'(accessed August 27, 2020).'},
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'multi-center observational study. medRxiv. 2020 Jan 1. doi: '
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