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 2,000 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 hospitalized 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
hospitalization, temperature normalization,
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 (5-8).
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 hospitalized patients with
severe COVID-19. Ongoing randomized clinical trials with
hydroxychloroquine should provide
a definitive answer regarding the alleged efficacy of
this combination and will assess its safety.
1. Wang M, Cao
R, Zhang L,
et al. Remdesivir and
chloroquine effectively inhibit
the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell
research 2020; 30:269-71. 2.
Al-Bari AA. Targeting
endosomal acidification by
chloroquine analogs as
a promising strategy for
the treatment of
emerging viral diseases.
Pharmacology research and perspectives. 2017;5:e00293 3.
Gautret P, Lagier
JC, Parola P,
et al. Hydroxychloroquine and
azithromycin as a treatment
of COVID-19: results
of an open-label
non-randomized clinical trial. International Journal of
Antimicrobial Agents 2020 (ahead of print).
4. Chen J, Liu D, Lui L, et al. A
pilot study of hydroxychloroquine in treatment of patients with common
coronavirus disease-19 COVID-19). Journal of Zhejiang University 2020; 03-03 5. Roques P, Thiberville SD, Dupuis-Maguiraga
L et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya
virus infection. Viruses, 2018:10:268 6. Tricou V, Minh NN, Van TP et al. A
randomized controlled trial of chloroquine for the treatment of
dengue in Vietnamese
adults. PLos Neglected
tropical diseases 2010; 4:e785.
7. Paton NI, Lee
L, Xu Y,
et al. Chloroquine for
influenza prevention: a
randomised, double-blind, placebo-controlled trial. Lancet Infectious
Diseases, 2011; 11:677-83 8. Paton NI,
Goodall RL, Dunn
DT, et al. Effects
of hydroxychloroquine on
immune activation and disease
progression among HIV-infected patients
not receiving antiretroviral
therapy: a randomized controlled trial. JAMA. 2012;308 (4):353-61.
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