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Hydroxychloroquine as a primary prophylactic agent against SARS-CoV-2 infection: A cohort study


Hydroxychloroquine has been proposed as a primary prophylactic agent against coronavirus disease 2019 (COVID-19). This study aimed to investigate if patients treated with hydroxychloroquine for a non-COVID-19 indication had a lower risk of verified infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared with matched controls.
A cohort comprising all persons in Denmark collecting hydroxychloroquine prescriptions in 2020 and 2019 (i.e., both during and before SARS-CoV-2 was confirmed in Denmark), matched by age and sex with controls, was studied. Data were collected using the Danish national registries, which contain complete information on patient health data, prescriptions, and microbiological test results. The main outcome was microbiologically verified SARS-CoV-2 infection.
In total, 5488 hydroxychloroquine users were matched with 54,486 non-users. At baseline, the groups differed in terms of diagnoses of pulmonary disease, cardiovascular disease, renal disease, gastrointestinal/metabolic disease, and dementia, as well as treatment with antirheumatic drugs. The final model was adjusted for these potential confounders. The use of hydroxychloroquine for non-COVID-19 indications was not associated with any change in confirmed SARS-CoV-2 (hazard ratio 0.90, 95% confidence interval 0.76–1.07). This result was robust in the propensity-score-matched sensitivity analysis.
This study, which is the largest to date to investigate the primary prophylactic effect of hydroxychloroquine against SARS-CoV-2, does not support any prophylactic benefit of hydroxychloroquine in the prevention of infection with SARS-CoV-2.


Chloroquine and hydroxychloroquine are in-vitro inhibitors of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in infected Vero cells (Liu et al., 2020, Wang et al., 2020, Yao et al., 2020). This contributed to the hypothesis that such drugs could be used as prophylaxis for SARS-CoV-2 infection and treatment of patients with coronavirus disease 2019 (COVID-19). Hydroxychloroquine is used for long-term treatment of several rheumatic diseases; it has a favorable safety profile (Ruiz-Irastorza et al., 2010, Ponticelli and Moroni, 2017) and a low cost (Ponticelli and Moroni, 2017), which is a key point when facing a pandemic.
Five randomized clinical trials have demonstrated a neutral effect of treatment with hydroxychloroquine in hospitalized patients with COVID-19 (Abd-Elsalam et al., 2020, Group et al., 2020, Self et al., 2020, Tang et al., 2020, WHO Solidarity Trial Consortium et al., 2020). Additionally, three randomized clinical trials reported no benefit of hydroxychloroquine as a postexposure prophylactic agent; two of these trials were against COVID-19 (Boulware et al., 2020, Mitjà et al., 2020) and the latter was against polymerase chain reaction (PCR)-verified SARS-CoV-2 infection (Barnabas et al., 2020).

Hydroxychloroquine has likewise been explored as a primary prophylactic agent against COVID-19 by two randomized trials (Abella et al., 2020, Rajasingham et al., 2020). However, both were stopped too early to reach a firm conclusion. Currently, four epidemiological studies investigating the primary prophylactic effect of hydroxychloroquine for SARS-CoV-2 infection have been identified (Gendelman et al., 2020, Jung et al., 2020, Bae et al., 2021, Ferreira et al., 2021). Three of these studies reported no effect (Gendelman et al., 2020, Jung et al., 2020, Bae et al., 2021), and the largest study reported a reduced risk of SARS-CoV-2 for persons with chronic hydroxychloroquine use (Ferreira et al., 2021). A recent meta-analysis concluded that there is a need for further evidence on the use of hydroxychloroquine for prophylaxis of COVID-19 (Singh et al., 2021). This large population-based cohort study, with substantially more events than previously published studies, investigated whether persons treated with hydroxychloroquine before the pandemic had a lower risk of PCR-confirmed SARS-CoV-2 infection compared with age- and sex-matched controls.


Study data
A cohort study was conducted based on nationwide Danish registry data. Data were collected from four registries: (i) the Danish National Patient Registry, which contains information on all admissions to Danish hospitals and hospital outpatient specialist clinic visits (Schmidt et al., 2015); (ii) the National Prescription Registry, which contains information on all prescriptions dispensed in Danish pharmacies [coded according to the Anatomical Therapeutic Chemical (ATC) classification system] (Pottegard et al., 2017); (iii) the Danish Central Personal Registry, which contains information on citizens of Denmark (e.g., age, sex, and vital status) (Schmidt et al., 2014); and (iv) the Danish Microbiology Database, where the Danish Departments of Clinical Microbiology (Voldstedlund et al., 2014) and Statens Serum Institut performed laboratory analysis, registration and release of the national SARS-CoV-2 surveillance data for the present study.

Study population
All patients residing in Denmark who collected a prescription for hydroxychloroquine (ATC P01BA02) in both 2020 and 2019 (i.e., initiated treatment before the pandemic emerged in Denmark) were included in the study. This approach was used to eliminate any impact of hydroxychloroquine use in attempts to treat COVID-19. Each recipient was matched randomly by birth year and sex with up to 10 non-treated controls by the Danish Health Data Authority. Information about comorbidities was obtained from the Danish National Patient Registry. Comorbidities were collected as classified in the Charlson comorbidity index (Quan et al., 2005). Grouping of comorbidities was performed as follows. Cardiovascular disease included heart failure, ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease. Gastrointestinal and metabolic disease included diabetes with and without complications; mild-, moderate- and severe liver disease; and peptic ulcer disease. Cancer included any malignancy (except malignant neoplasm of skin) and solid metastatic tumors. Pulmonary disease was defined by the Charlson comorbidity index, with interstitial pulmonary diseases also included. Comorbidities included in this study and their grouping are illustrated in Table S1 (see online supplementary material). Only comorbidities or groups of comorbidities with prevalence among the study population ≥5% were included in this study. Diagnoses of ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes tachycardia were collected to assess safety.
All subjects were linked to the National Prescription Registry to obtain information on the pharmaceuticals used for outpatient treatment of rheumatoid arthritis and systemic lupus erythematosus in Denmark (ATC code): hydroxychloroquine (P01BA02), methotrexate (L04AX03), sulfasalazine (A07EC01), systemic corticosteroids (H02AB), ciclosporin (L04AD01) and azathioprine (L04AX01). All subjects were linked to the Danish Microbiology Database to access their positive SARS-CoV-2 test results.
The observation time commenced at the time of the first confirmed case of SARS-CoV-2 in Denmark (27 February 2020), and lasted until either (i) time of laboratory-confirmed SARS-CoV-2 infection; (ii) death; or (iii) end of follow-up (30 April 2021), whichever came first.


Hydroxychloroquine was the intervention investigated. To avoid bias, users of the drug in both 2019 and 2020 were analyzed. Additionally, controls who started hydroxychloroquine in 2020 were excluded (n = 11).


The primary outcome measure was a PCR- or antigenic-verified SARS-CoV-2 infection during the study period (27 February–30 April 2021). The secondary outcome was hospitalization for >12 h within 14 days of a positive SARS-CoV-2-test. buy hydroxychloroquine | buy hydroxychloroquine online | buy hydroxychloroquine australia | buy hydroxychloroquine canada | buy hydroxychloroquine Amazone | buy hydroxychloroquine Online Singapore |

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