Clinical data on 4-aminoquinones and SARS-CoV-2
In the early stages of the pandemic, the National Health Commission of
China incorporated 4-aminoquinones into the treatment guidelines of
COVID-19 after Chinese preliminary data demonstrated tolerability and
efficacy of chloroquine in treating COVID-19.[2] The expectations
for the effectiveness of these medications sharply increased after
Gautret et al. published results from their small, open-label,
non-randomized clinical trial from a single-center in Marseilles,
France.[30] This trial concluded that hydroxychloroquine given at a
dose of 600 mg a day in combination with azithromycin was effective in
viral load reduction and virus elimination of SARS-CoV-2 as measured by
nasopharyngeal PCR in patients across disease severity. The article
received criticism for its statistical methods, and particularly for
excluding 6 out of the 26 patients who received hydroxychloroquine and
were lost to follow up or had a poor outcome. Shortly thereafter, the
U.S. Food and Drug Administration (FDA) issued an emergency use
authorization that allowed the use of hydroxychloroquine in patients
hospitalized due to COVID-19 when clinical trials were not available or
participation in clinical trials was not feasible.[31] Other
countries, including Brazil, France, Italy, Netherlands, and South Korea
issued similar recommendations.
Between March and May, 2020, the period of our trial’s design and
recruitment, a myriad of hydroxychloroquine clinical studies were
performed. The studies were primarily retrospective analysis reporting
on the clinical outcomes of its use in hospitalized patients. In many
cases, these studies were subject to confounders and selection biases.
Data from randomized controlled trials has more recently become
available (Table 1).
A retrospective analysis of hospitalized, non-mechanically ventilated
patients across all U.S. Veteran’s Health Administration Medical Centers
revealed an association between the use of hydroxychloroquine and an
increase in in-hospital mortality.[32] The authors did not specify
the excess cause of death in this subgroup, but it did not seem to
derive from worse respiratory failure, given that rates of mechanical
ventilation were similar between subgroups. An observational study in
France comparing 84 hydroxychloroquine treated individuals with 89
patients treated with usual care found similar survival without transfer
to the ICU at day 21 in both groups.[33] This trial pre-specified
treatment groups prior to hospital admission to minimize selection bias.
A multicenter retrospective study in the United States included 1438
patients from 25 hospitals failed to demonstrate a reduction in
in-hospital mortality in patients treated with hydroxychloroquine,
azithromycin or both. Combination treatment with hydroxychloroquine and
azithromycin was associated with more frequent cardiac arrest (HR 2.13,
CI 1.12 – 4.05).[34] A single center study from New York City found
no association between hydroxychloroquine and the composite end point of
intubation or death (HR 1.04, CI 0.82 – 1.32) in 1376 patients who
received usual care or hydroxychloroquine alone.[35] The Henry Ford
Hospital Study, a retrospective cohort study of 2541 patients, reported
a mortality benefit in patients receiving hydroxychloroquine.[36]
This study has been criticized for potential confounding factors
including the more frequent use of corticosteroids and tocilizumab in
hydroxychloroquine treatment arms, with corticosteroids now recognized
as an effective form of treatment in hospitalized patients requiring
supplemental oxygen.[37]
A retrospective analysis of a multinational registry including over
96,031 subjects from 671 hospitals in six continents comparing four
groups, chloroquine or hydroxychloroquine with and without a macrolide,
to usual care reported an increase in hospital mortality and new
ventricular arrhythmias with use of hydroxychloroquine and chloroquine
with or without macrolide.[38] This study was soon retracted due to
questions over data integrity as a significant amount of data provided
by a private company, Surgisphere, appeared to have large discrepancies
and was not released for independent review citing contractual
limitations.
In a retrospective study of critically ill, mechanically ventilated
patients with COVID-19, hydroxychloroquine was associated with a
substantial decrease in mortality (18.8% in the hydroxychloroquine
group versus 47.4% in the control group) and interleukin-6
concentrations.[39] The authors did not report criteria for
hydroxychloroquine use and selection bias is an important concern when
interpreting these results. Preliminary results of the randomized
controlled multicenter RECOVERY trial comparing 1561 patients treated
with high-dose hydroxychloroquine to 3155 patients on usual care
revealed hydroxychloroquine was not associated with reductions in 28-day
mortality but rather with increased length of hospital stay and
increased risk of progression to invasive mechanical
ventilation.[40]
After review of these trials, the U. S. FDA revoked its Emergency Use
Authorization of chloroquine and hydroxychloroquine to treat
hospitalized COVID-19 patients. Subsequently, the World Health
Organization discontinued the SOLIDARITY trial of hydroxychloroquine
treatment in hospitalized COVID-19 patients after interim results
revealed little or no reduction in mortality and concerning safety
signals, albeit without “solid evidence of increase in mortality.”
A randomized controlled trial addressing mild to moderate hospitalized
COVID-19 patients also failed to show that hydroxychloroquine alone or
in combination with azithromycin improves clinical status compared to
usual care.[41] The first randomized multicenter clinical trial
evaluating the effect of hydroxychloroquine (n=75) in comparison to
usual care alone (n=75) in mild to moderate COVID-19 did not show
differences in the probability of SARS-CoV-2 PCR negative conversion or
alleviation of symptoms by day 28 of follow up.[42] The median of 16
days delay between onset of symptoms and randomization could have biased
the results towards the non-intervention group.
A recent randomized, double-blind, placebo-controlled clinical trial for
treatment of symptomatic non-hospitalized patients with COVID-19
investigated a higher dose of hydroxychloroquine (800mg plus 600mg six
to 8 hours later and 600mg daily for 4 days). This trial demonstrated
that hydroxychloroquine did not substantially reduce symptom severity in
outpatients with early, mild COVID-19. Adverse events were significantly
higher in hydroxychloroquine group with gastrointestinal symptoms being
most commonly reported. Of note, some limitations included only 58% of
patients had laboratory confirmation of SARS-CoV-2 due to testing
shortages.[43]
Conflicting results from small clinical trials and a retrospective study
on the benefits of hydroxychloroquine with and without azithromycin have
been reported. [30, 44-48] Such studies were frequently unpowered
and lacked a comparison group.[44, 45, 48] Moreover, the inclusion
of individuals with mild or no symptoms and characteristics associated
with better prognosis support the evidence that the prognosis in mild to
moderate COVID-19 is overall good and treatment is unlikely to benefit
these patients.[49]
The use of hydroxychloroquine as a prophylactic agent has been less
studied. Through a creative recruitment process utilizing internet-based
self-referral and online follow up surveys, Boulware et al.randomized asymptomatic adult individuals from Canada and the U. S. who
had a high or moderate-risk exposure to confirmed cases of COVID-19 to
hydroxychloroquine or placebo.[50] Hydroxychloroquine did not
prevent illness compatible or confirmed to be COVID-19 infection and was
associated with increased mild adverse reactions. In light of the
overall younger (median age 40) and healthier population recruited,
mostly women (51.6%), the question remains if more at risk populations
would benefit from the intervention.