No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection

Abstract

The COVID-19 epidemic is the worst worldwide pandemic in a century with more than 500,000 cases and 25,000 deaths so far. In France, more than 30,000 cases have been reported up to March 27, and nearly 2000 have died. Pending the availability of a vaccine, there is a critical need to identify effective treatments and a number of clinical trials have been implemented worldwide. Chloroquine analogs have been shown to inhibit the acidification of endosomes and to exhibit in vitro a non-specific antiviral activity at high micromolar concentration against a broad range of emerging virus (HIV, dengue, hepatitis C, chikungunya, influenza, Ebola, SARS and MERS viruses) and more recently COVID-19 [1], [2]. In France, following the results of a clinical study in Marseille, there is considerable interest for the use of hydroxychloroquine to treat COVID-19 disease, and the French Ministry of Health recently allowed the use of hydroxychloroquine to treat COVID-19 disease pending the results of ongoing clinical trials [3]. In their study, Gautret et al. reported a 100% viral clearance in nasopharyngeal swabs in 6 patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin [3]. This rate of viral clearance was lower with hydroxychloroquine alone (57.1%) and was only 12.5% in patients who did not receive hydroxychloroquine (P  < 0.001). Such a rapid and full viral clearance was quite unexpected and we wished to assess in a prospective study virologic and clinical outcomes of 11 consecutive patients hospitalised in our department who received hydroxychloroquine (600 mg/d for 10 days) and azithromycin (500 mg day 1 and 250 mg days 2 to 5) using the same dosing regimen reported by Gautret et al. [3]. There were 7 men and 4 women with a mean age of 58.7 years (range: 20–77), 8 had significant comorbidities associated with poor outcomes (obesity: 2; solid cancer: 3; hematological cancer: 2; HIV-infection: 1). At the time of treatment initiation, 10/11 had fever and received nasal oxygen therapy. Within 5 days, one patient died, two were transferred to the ICU. In one patient, hydroxychloroquine and azithromycin were discontinued after 4 days because of a prolongation of the QT interval from 405 ms before treatment to 460 and 470 ms under the combination. Mean through blood concentration of hydroxychloroquine was 678 ng/mL (range: 381–891) at days 3–7 after treatment initiation. Repeated nasopharyngeal swabs in 10 patients (not done in the patient who died) using a qualitative PCR assay (nucleic acid extraction using Nuclisens Easy Mag®, Biomerieux and amplification with RealStar SARS CoV-2®, Altona), were still positive for SARS-CoV2 RNA in 8/10 patients (80%, 95% confidence interval: 49–94) at days 5 to 6 after treatment initiation. These virologic results stand in contrast with those reported by Gautret et al. and cast doubts about the strong antiviral efficacy of this combination. Furthermore, in their report Gautret et al. also reported one death and three transfers to the ICU among the 26 patients who received hydroxychloroquine, also underlining the poor clinical outcome with this combination. In addition, a recent study from China in individuals with COVID-19 found no difference in the rate of virologic clearance at 7 days with or without 5 days of hydroxychloroquine, and no difference in clinical outcomes (duration of hospitalisation, temperature normalisation, radiological progression) [4]. These results are consistent with the lack of virologic or clinical benefit of chloroquine in a number of viral infections where it was assessed for treatment or prophylaxis with sometimes a deleterious effect on viral replication [5], [6], [7], [8]. In summary, despite a reported antiviral activity of chloroquine against COVID-19 in vitro, we found no evidence of a strong antiviral activity or clinical benefit of the combination of hydroxychloroquine and azithromycin for the treatment of our hospitalised patients with severe COVID-19. Ongoing randomised clinical trials with hydroxychloroquine should provide a definitive answer regarding the alleged efficacy of this combination and will assess its safety. Ethical Approval All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments. Disclosure of interest The authors declare that they have no competing interest.