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COVID-19: Chloroquine and hydroxychloroquine as potential therapies against COVID-19

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KEY POINTS • At the moment there is no effective treatment for COVID-19 adequately validated. • Chloroquine and hydroxychloroquine have been effective in vitro against COVID-19 but the available data do not confirm their usefulness from a clinical perspective • Nowadays, we have information from four clinical trials (one not published yet) and several observational studies (one not published and another one pending of retraction). • Three out of four clinical trials do not show any benefit with hydroxychloroquine over standard care as a treatment or prophylaxis. The other clinical trial suggests data in favour of hydroxychloroquine on variables of limited clinical relevance, presenting important methodological concerns and biases that undermine its credibility. • None of the four observational studies with larger sample size, clinically relevant outcomes and more sounded statistical approach have showed any benefits of hydroxychloroquine, with or without azithromycin, versus the control groups. The results of the more relevant observational study have been challenged due to database inconsistencies and three authors have asked for retraction. • Serious adverse events (prolongation of the QT interval and arrhythmias, some with fatal outcome) have been linked to the concomitant use of hydroxychloroquine and azithromycin. Health authorities warn about the risk associated to their use.
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REPORT (version 6) June 5, 2020
The current SARS-CoV-2 (COVID-19) coronavirus pandemic is posing many health management
challenges with multiple uncertainties. One of the most relevant is focused on the most suitable
pharmacological therapy for cure and prophylaxis. Currently, there is no specific drug treatment for
COVID-19 that has demonstrated efficacy and safety in high- quality studies (1). However, different
options are being proposed from an experimental approach. One of them is the use of chloroquine
(CRQ) and its derivatives, basically hydroxychloroquine (HCQ).
INTRODUCTION
On 28 May, the Spanish Agency for Medicines and Healthcare Products (AEMPS) updated a
document analysing different available alternatives, existing presentations, degree of evidence,
access requirements, proposed doses and most common adverse effects for every assessed drug (2).
The chloroquine/hydroxychloroquine section provides interesting information taking into account
Chloroquine and hydroxychloroquine as potential
therapies against COVID-19
Luis Carlos Saiz, PharmD, PhD.
Innovation and Organization Unit. Navarre Health Service, Spain.
KEY MESSAGES
At the moment there is no effective treatment for COVID-19 adequately validated.
Chloroquine and hydroxychloroquine have been effective in vitro against COVID-19 but the
available data do not confirm their usefulness from a clinical perspective
Nowadays, we have information from four clinical trials (one not published yet) and
several observational studies (one not published and another one pending of retraction).
Three out of four clinical trials do not show any benefit with hydroxychloroquine over standard
care as a treatment or prophylaxis. The other clinical trial suggests data in favour of
hydroxychloroquine on variables of limited clinical relevance, presenting important
methodological concerns and biases that undermine its credibility.
None of the four observational studies with larger sample size, clinically relevant outcomes
and more sounded statistical approach have showed any benefits of hydroxychloroquine,
with or without azithromycin, versus the control groups. The results of the more relevant
observational study have been challenged due to database inconsistencies and three authors
have asked for retraction.
Serious adverse events (prolongation of the QT interval and arrhythmias, some with fatal
outcome) have been linked to the concomitant use of hydroxychloroquine and azithromycin.
Health authorities warn about the risk associated to their use.
2
these aspects, highlighting its important role against malaria, lupus or rheumatoid arthritis.
With regard to the scientific evidence, CRQ and HCQ have shown in vitro activity against SARS-CoV-
2, but so far no published clinical trials have been carried out to confirm this effect. In other
contexts, CRQ has not been shown to be effective in treating other viruses in animal or human
models such as influenza, dengue or Chikungunya (2). Despite the limited evidence, the FDA has
issued an emergency use authorization for the use of CRQ and HCQ in hospitalized patients with
COVID-19 (3).
A CRITICAL READING OF THE CLINICAL EVIDENCE
Lack of information on drug treatments against COVID-19 at the pandemic onset has initially led to a
wide dissemination of unpublished studies and observational designs with low quality evidence (e.g.
case series). Once this first stage has been overcome, this report will assess from now on only those
clinical trials and observational studies that meet two basic requirements: publication according to a
peer review process and comparative information provided with an appropriate control arm.
At present, numerous clinical trials are underway with CRQ and HCQ (4) such as SOLIDARITY (5) or
EPICOS (6), among the most important projects in Spain. Nevertheless, the first published article
mentioning the use of CRQ in patients with COVID-19 was a letter to the editor (7) where no
verifiable data is provided about its potential benefits in more than 100 infected patients, as stated in
that document.
Table 1. Hydroxychloroquine studies with available results in COVID-19 patients.
Clinical trials
Design
Patients
Main
outcome
Result
Comments
Chen (8)
Open
Controlled
Randomized
1:1
Unicentric
N=30 (15 HCQ, 15
control) Age, mean 50
years, males 70%,
COVID-19
admission, with no serious
concomitant disease
Viral clearance
at Day 7 or
death in two
weeks
No differences in
the main
outcome
HCQ (86,7%)
STD (93,3%)
Clinical trial with low
statistical power and
no positive results. All
patients improve their
basal condition.
Chen (9)
Open
Controlled
Randomized
1:1:1
Unicentric
N=62 (31 HCQ, 31
control) Age, mean 45
years, males 47%, COVID-
19 with pneumonia but
without serious hypoxia
Time to viral
clearance and
T cell recovery
time
No data provided
on main
outcomes
NOT PUBLISHED YET
Clinical trial with wide
discrepancy between
protocol and article.
Uncertain findings in
secondary outcomes.
Tang (10)
Open
Controlled
Randomized
1:1
Multicentric
N=150 (75 HCQ, 75 control)
Age, mean 46 years,
males 55%, mild-
moderate COVID-19
admission.
Viral clearance
within 28 days
No differences in
the main
outcome
HCQ (85,4%)
STD (81,3%)
Clinical trial with no
positive results.
Uncertain post-hoc
finding.
Boulware
(11)
Double blind
Controlled
Randomized
1:1
N=821 (414 HCQ, 407
control)
Age, median 41 years,
males 48%, adults exposed
to COVID-19 patients
Confirmed or
compatible
illness with
COVID-19
within 14 days
No differences in
the main
outcome
HCQ (11,8%)
Placebo (14,3%)
Clinical trial with no
positive results.
Non-serious adverse
events more common
with HCQ (40% vs 17%)
Other studies
Design
Patients
Main
outcome
Result
Comments
3
Gautret (12)
Not
controlled
Not
randomized
With external
control group
N=42 (26 HCQ, 16
control) Age, mean 45
years, males 42%,
COVID-19,
any level of severity
Viral clearance
at Day 6
HCQ+AZT (100%)
HCQ (57,1%)
No HCQ (12,5%)
N=36 assessed
Quality of evidence low
Some patients
excluded
Publicación bias.
Conflict of interests.
Gautret (13)
Not
controlled
Not
randomized
N=80
Age, median 53 years,
males 53%, COVID-19,
with or without
comorbidities
Clinical course
Contagiousness
Length of stay
in the ID ward
81,3% favourable
outcome; 83%
negative PCR at
Day 7; Mean
lenght of stay of
4,6 days
Quality of evidence low
6 patients already
assessed in other study
Protocol not provided.
Molina (14)
Not
controlled
Not
randomized
N=11
Age, mean 59 years,
males 64%, COVID-19, with
or without comorbidities
Viral clearance
at Day 5/6
HCQ+AZT (20%)
Quality of evidence low
Protocol not provided.
Magagnoli (15)
Not
randomized
Retrospectiv
e
PSA
N=368 (97 HCQ, 113 HCQ
+ AZT, 158 control)
Median age 69 years,
males 100%, COVID-19,
hospitalized
Mortality and
need of
mechanical
ventilation
Mortality:
HCQ 27.8%,
HCQ+AZT 22.1%,
control 11.4%.
Ventilation: ND
NOT PUBLISHED YET
Observational study
No positive results
Protocol not provided
Mahévas (16)
Not
randomized
Target trial
simulation
PSA
N=181 (84 HCQ, 89
control)
Median age 60 years,
males 72%, COVID-19 with
pneumonia and need of
external oxigen.
Survival with
no admission
at ICU within
21 days since
inclusion
Survival with no
admission at ICU
HR 0,9 (0,4-2,1)
Observational study
No positive results
Protocol not provided
Geleris (17)
Not
randomized
PSA
N=1085 (811 HCQ, 274
control)
Age > 60 years (63%),
males 59%, COVID-19,
hospitalized
Intubation +
mortality
Intubation +
mortality
HR: 0.97 (0.74-
1.28). Propensity
score-matched
Observational study
No positive results
Protocol not provided
Rosenberg (18)
Not
randomized
Retrospectiv
e Cox model
N=1438 (735 HCQ+AZT,
271 HCQ, 211 AZT, 221
control)
Median age 63 years,
males 60%, COVID-19
hospitalized
In-hospital
mortality
Mortality (HR)
1.35 (0.76-2.40)
1.08 (0.63-1.85)
0.56 (0.26-1.21)
No differences
Observational study
No positive results
Protocol not provided
AZT: Azithromycin; HCQ: Hydroxychloroquine; ICU: Intensive Care Unit; HR: Hazard Ratio; ID: Infectious Disease; ND: No
differences; PSA: Propensity Score Adjustment; STD: Standard Care.
Nowadays, information can be extracted from for clinical trials (8,9,10,11), one of which have not
been published yet, and seven studies with an observational design (11-18), one not published (Table
1). An additional observational study is currently in the process of retraction (19).
1.
CLINICAL TRIALS
The study by Chen J et al. (8) must be emphasized because it is the first published trial in patients
with COVID-19 that randomizes patients to receive HCQ or standard treatment. The protocol has not
been accessed. The sample size is small, although basal characteristics appear to be balanced in both
Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilot study of hydroxychloroquine in treatment of
patients with common coronavirus disease-19 (COVID-19).
J of Zhejiang University. 2020;3. Doi: 10.3785/j.issn.1008-9292.2020.03.03.
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arms. At the end of the two-week follow-up, all patients improved their condition without differences
in the estimated variables. The efficacy of HCQ against COVID- 19 remains unproven, although larger
studies are needed to confirm the results.
On March 31, the results of another Chinese clinical trial, Chen Z et al., not published, were released
(9). The process of randomization and blinding is unclear. The positive findings favouring HCQ in
improving body temperature and cough do not seem convincing due to premature
discontinuation of the study, discrepancies between protocol and article in the reported variables
and age range of patients (20), as well as a lack of results for the HCQ group 200mg/day. It is also
a matter of discussion whether a placebo was finally used and if observed differences are or not
clinically significant.
The results of another Chinese clinical trial, Tang W et al., have already been published (10). This is
the study with the largest sample size whose results are known. There were no differences favouring
HCQ in the main variable (viral clearance within 28 days) nor in most of the secondary variables (viral
clearance at other time points, improvement in clinical symptoms and lymphocyte count). The
proportion of adverse events was significantly higher in the HCQ group (30.0%, two of them were
serious) than in the control group (8.8%). Potential post-hoc and C- reactive protein normalization
findings should be confirmed in further studies.
Finally, a randomized, double-blind, placebo-controlled clinical trial (Boulware DR et al.) has been
conducted to evaluate the effect of HCQ as prophylaxis for COVID-19 in adults with close contact of
infected patients (11). Participants received HCQ or placebo for 4 days after exposure and the
incidence of new cases of COVID-19 was estimated within 14 days. No statistically significant
differences were found in this outcome (11.8% vs. 14.3%). As for adverse events, these were more
frequent problems in the HCQ group (40.1%) than in the control group (16.8%), although no serious
adverse events were recorded. In conclusion, HCQ has not shown a protective effect when used in a
post-exposure prophylaxis setting.
2.
OBSERVATIONAL STUDIES
A first study by Gautret et al. (12) has significant limitations that need to be taken into account when
considering its scientific contribution. The main limitation stems from the fact that it was not originally
conceived as a comparative study and it was eventually analysed as such. The lack of randomization and
blinding are additional shortcomings. Secondly, the exclusion of six patients from the analysis does not
seem adequately justified, favouring the HCQ group. On the other hand, all three groups of participants
to be compared (HCQ, HCQ+AZT, controls) are highly heterogeneous in terms of inclusion criteria,
recruitment centres and age range. The criteria for adding AZT was optional, just depending on the
clinical judgment of the professional. The main variable is short-term and the measurement time points
foreseen in the protocol were superseded with no justification. Lack of viral load data at a given time
point were not treated equally for both groups. It is not possible to confirm whether viral load data
translate into more relevant clinical consequences (e.g. discharge, ICU admission, mortality, serious
adverse events). Finally, the publication presents significant conflicts of interest. One of the study
authors (Rolain JM) is the editor-in-chief of the journal where the paper was published. Likewise, the
sponsor (Fondation Méditerranée Infection) has among its recognized partners Sanofi Aventis
(https://www.mediterranee-infection.com/en/institute/partners/), who in turn markets HCQ in France
5
(Plaquenil®).
The same research team has released a second study sharing some of the first article methodological
concerns (13). The study authored by Molina et al. presents a small cohort of 11 COVID-19 patients
treated with the same therapeutic strategy previously used by Gautret et al. It obtained clearly
discordant results, achieving a viral clearance at Day 5-6 in only two out of ten (20%) of total participants
(14).
The results of four other observational studies (15-18) with larger sample sizes, clinically relevant
variables (mortality, need for intubation or mechanical ventilation) and a more robust statistical
approach have subsequently become available. None of them have found benefits related to the
administration of HCQ or CRQ, with or without macrolides, in the estimated main outcomes.
Finally, the far-reaching study by Mehra et al. had incorporated the largest sample of patients so far
(19), suggesting a higher mortality associated with the use of HCQ and CRQ in the context of COVID-
19 infection. However, after significant concerns have been raised about the integrity of the
database, The Lancet has issued an official expression of concern and three out of the four authors
have already requested a retraction of the article (21). Among the desirable lessons the scientific
community can draw from this particular case, we can emphazise the need for full transparency in
the data supporting publications, the risk of over-accelerating the publication process, the caution to
be exercised in relation to the expectations placed on big data technology and the necessary co-
responsibility of all article authors at supervising their own databases.
Considering the available information as a whole, it can be concluded that data remain insufficient to
recommend CRQ and HCQ as a treatment for COVID-19 up to now (1).
RISK OF ADVERSE EVENTS
The prolongation of the QT interval has been associated with an increased risk of torsade de pointes
and sudden death. Both CRQ and HCQ have the ability to prolong the QT interval, which can lead to a
serious interaction when given with other drugs that have the same effect (e.g. azithromycin) (22).
Currently there is very limited information on the safety of their concomitant use (23) and it is not
recommended out of a clinical trial setting (1).
In this regard, a cohort study with 90 COVID-19 hospitalized patients with pneumonia and treated
with HCQ + azithromycin has shown that HCQ increases the QTc interval risk, being even higher when
azithromycin was given concomitantly (24). In addition, an analysis of the HCQ cardiovascular
adverse events reported to the French pharmacovigilance database from 27 March to 10 April 2020
was performed. Forty-three events were recorded, some in combination with azithromycin, including
seven sudden deaths [3 recovered by electroshock], a dozen arrhythmias/syncope and other cardiac
problems that evolved favourably after the treatment was stopped (25). The AEMPS (26) and the
European Medicines Agency (27) have warned that CRQ and HCQ can cause serious heart rhythm
problems, mostly with high doses and if given simultaneously with other drugs sharing this same
adverse effect. Serious neuropsychiatric adverse events have also been reported. Thus, the AEMPS
explicitly discourages the combination of HCQ with drugs sharing the same risk (26). The FDA
recommends not using it outside of the hospital setting or a clinical trial (28). Should HCQ were
massively used in the future, it is foreseeable that some patients will suffer rare but potentially very
serious adverse events, such as the aforementioned arrhythmias, skin reactions or fulminant liver
failure (29).
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CONFLICT OF INTEREST
The author declares no conflict of interest.
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ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Article
Background Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days. Results We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported. Conclusions After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.)
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Objective To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). Design Multicentre, open label, randomised controlled trial. Setting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. Participants 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). Interventions Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). Main outcome measure Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. Results Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. Conclusions Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. Trial registration ChiCTR2000029868.
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Objective To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen. Design Comparative observational study using data collected from routine care. Setting Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. Participants 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care. Interventions Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group). Main outcome measures The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment. Conclusions Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.
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Importance Administration of hydroxychloroquine with or without azithromycin for the treatment of coronavirus disease 2019 (COVID-19)–associated pneumonia carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias. Objective To characterize the risk and degree of QT prolongation in patients with COVID-19 in association with their use of hydroxychloroquine with or without concomitant azithromycin. Design, Setting, and Participants This was a cohort study performed at an academic tertiary care center in Boston, Massachusetts, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal polymerase chain reaction test result and clinical findings consistent with pneumonia who received at least 1 day of hydroxychloroquine from March 1, 2020, through April 7, 2020. Main Outcomes and Measures Change in QT interval after receiving hydroxychloroquine with or without azithromycin; occurrence of other potential adverse drug events. Results Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin; 44 (48.9%) were female, and the mean (SD) body mass index was 31.5 (6.6). Hypertension (in 48 patients [53.3%]) and diabetes mellitus (in 26 patients [28.9%]) were the most common comorbid conditions. The overall median (interquartile range) baseline QTc was 455 (430-474) milliseconds (hydroxychloroquine, 473 [454-487] milliseconds vs hydroxychloroquine and azithromycin, 442 [427-461] milliseconds; P < .001). Those receiving concomitant azithromycin had a greater median (interquartile range) change in QT interval (23 [10-40] milliseconds) compared with those receiving hydroxychloroquine alone (5.5 [−15.5 to 34.25] milliseconds; P = .03). Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. The likelihood of prolonged QTc was greater in those who received concomitant loop diuretics (adjusted odds ratio, 3.38 [95% CI, 1.03-11.08]) or had a baseline QTc of 450 milliseconds or more (adjusted odds ratio, 7.11 [95% CI, 1.75-28.87]). Ten patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of torsades de pointes. Conclusions and Relevance In this cohort study, patients who received hydroxychloroquine for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc. Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.
Article
Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1,9) days in HCQ group, which is comparable to that in the control group [2 (1,4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0,2) day after hospitalization, which was also comparable to that in the control group [1 (0,3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.
Article
Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events. Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19. Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020. Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither. Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation). Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings. Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
Article
Background Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use. Methods We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score. Results Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses. Conclusions In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.)
Article
Background We need an effective treatment to cure COVID-19 patients and to decrease virus carriage duration. Methods We conducted an uncontrolled non-comparative observational study in a cohort of 80 relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin over a period of at least three days, with three main measurements: clinical outcome, contagiousness as assessed by PCR and culture, and length of stay in infectious disease unit (IDU). Results All patients improved clinically except one 86 year-old patient who died, and one 74 year-old patient still in intensive care. A rapid fall of nasopharyngeal viral load was noted, with 83% negative at Day7, and 93% at Day8. Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day5. Consequently patients were able to be rapidly discharged from IDU with a mean length of stay of five days. Conclusion We believe there is urgency to evaluate the effectiveness of this potentially-life saving therapeutic strategy at a larger scale, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold and to decrease duration of carriage and avoid the spread of the disease. Furthermore, the cost of treatment is negligible.