Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019 disease.

BACKGROUND: Severe acute respiratory coronavirus 2 (SARS-CoV-2) has caused a devastating worldwide pandemic. Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2, but clinical data supporting HCQ for coronavirus disease 2019 (COVID-19) are limited.
METHODS: This was a retrospective cohort study of hospitalized patients with COVID-19 who received ≥1 dose of HCQ at two New York City hospitals. We measured incident Grade 3 or 4 blood count and liver test abnormalities, ventricular arrhythmias, and vomiting and diarrhea within 10 days after HCQ initiation, and the proportion of patients who completed HCQ therapy. We also describe changes in Sequential Organ Failure Assessment hypoxia scores between baseline and day 10 after HCQ initiation and in-hospital mortality.
RESULTS: None of the 153 hospitalized patients with COVID-19 who received HCQ developed a sustained ventricular tachyarrhythmia. Incident blood count and liver test abnormalities occurred in <15% of patients and incident vomiting or diarrhea was rare. Eighty-nine percent of patients completed their HCQ course and three patients discontinued therapy because of QT prolongation. Fifty-two percent of patients had improved hypoxia scores 10 days after starting HCQ. Thirty-one percent of patients who were receiving mechanical ventilation at the time of HCQ initiation died during their hospitalization, compared to 18% of patients who were receiving supplemental oxygen but not requiring mechanical ventilation, and 8% of patients who were not requiring supplemental oxygen. Co-administration of azithromycin was not associated with improved outcomes.
CONCLUSIONS: HCQ appears to be reasonably safe and tolerable in most hospitalized patients with COVID-19. However, nearly one-half of patients did not improve with this treatment, highlighting the need to evaluate HCQ and alternate therapies in randomized trials.

Introduction

Severe acute respiratory coronavirus 2 (SARS-CoV-2) emerged as a cause of lethal illness in December 2019 [1]. In six months, this novel coronavirus caused a worldwide pandemic, infecting over 8 million people and killing over 450,000 people [2]. New York City (NYC) became the epicenter for the disease caused by this virus (COVID-19), with more cases and deaths from this infection than any other city in the world [3]. There are no proven effective therapies for COVID-19 that are available for widespread use. Although the investigational drug remdesivir demonstrated promising preliminary results in one trial [4], its availability is limited and it has yet to be approved by the U.S. Food and Drug Administration (FDA) or European Medicines Agency [5]. Thus, additional data on potential therapies are urgently needed.

Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2 and is an FDA-approved medication for malaria and rheumatologic disorders [6, 7]. However, clinical data supporting its use for COVID-19 are limited to small case series and trials in patients with mild illness, including a study suggesting potential benefit when co-administered with azithromycin [8, 9]. Recent observational studies have not identified an association between HCQ use and improved clinical outcomes in hospitalized patients with COVID-19, although patients who received HCQ were more severely ill than those who did not receive HCQ in these studies [10, 11]. There are also limited data characterizing the safety and tolerability of HCQ for acutely ill patients. Potential serious adverse effects include ventricular arrhythmias due to QT prolongation and hematologic and gastrointestinal toxicity [12-17]. Although large clinical trials to definitively evaluate the efficacy and safety of HCQ for hospitalized patients with COVID-19 have been initiated, results from these trials are not yet available. In the meantime, clinical data describing the use of HCQ for COVID-19 in acutely ill patients are urgently needed. Here we report the safety, tolerability, and clinical outcomes of HCQ for hospitalized patients with COVID-19 during the first three weeks of this outbreak in NYC.

Methods

Study population

This retrospective observational study consisted of all patients who were hospitalized at NewYork-Presbyterian Hospital/Weill Cornell Medical Center (NYPH/WCMC) and affiliated Lower Manhattan Hospital (NYPH/LMH), had a positive reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between March 05 2020 (date of the first case) and March 25 2020, and had treatment with HCQ initiated during their admission. NYPH/WCMC is a quaternary care referral center and NYPH/LMH is a community hospital. Both hospitals are in Manhattan. Patients who were enrolled in a clinical trial of remdesivir or who were prescribed HCQ chronically were included in the safety and tolerability cohort but excluded from the clinical outcomes cohort (Fig 1).

Fig 1

Study flow diagram.

Institutional guidance was to offer HCQ to hospitalized patients with COVID-19 who did not have imminent plans for hospital discharge and who had a corrected QT (QTc) interval of <500 msec. After review of pharmacokinetic data [7], a dosage of 600 mg of HCQ every 12 hours for two doses, followed by 400 mg daily for four additional days, was recommended. If patients were able to be discharged prior to completion of this treatment course, HCQ was discontinued upon hospital discharge. Hospitalized patients with COVID-19 who did not receive HCQ generally had mild illness and short inpatient admissions, and thus were not considered to be a suitable control group.

Nasopharyngeal swab specimens were used to assess for SARS-CoV-2 by RT-PCR. This testing was conducted by the New York City Department of Health and Mental Hygiene until March 10 2020 and after March 11 it was conducted at NYPH/WCMC.

Data collection

Data were retrospectively abstracted manually from the electronic medical record using a quality-controlled protocol and entered into a REDCap database [18]. A random sampling of 10% of cases to monitor quality yielded high interrater reliability (mean Cohen’s kappa of 0.92; [19]). Data included demographics, comorbidities, social characteristics, outpatient medications, presenting symptoms, vital signs (the highest temperature, heart rate, and respiratory rate, and the lowest systolic blood pressure) on the day HCQ was initiated, chest radiography results, administration of HCQ and antimicrobial agents, and outcomes. The study was approved by the Institutional Review Board (#20–03021681) at Weill Cornell Medicine with a waiver of informed consent.

Safety

We recorded the QTc interval using Bazett’s formula for patients who had an electrocardiogram (EKG) performed prior to HCQ initiation [20]. If an EKG was also performed between 1–10 days after HCQ initiation, we compared the baseline QTc interval to the follow-up QTc interval. We also reviewed results of complete blood count and liver tests from the onset of HCQ initiation until 10 days after HCQ initiation. We applied the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0, to assess for incident Grade 3 or 4 neutropenia, lymphopenia, anemia, thrombocytopenia, and aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin elevations during this time period [21]. Finally, we recorded the proportion of patients who developed incident kidney failure requiring renal replacement therapy between days 1–10 after HCQ initiation.

Tolerability

We assessed the proportion of patients who completed their scheduled treatment course, defined as completing the 5-day course or continuing HCQ until the day of discharge. We also reviewed the reasons for discontinuing HCQ. In order to assess incident vomiting or diarrhea, daily inpatient progress notes for each patient were reviewed from the day of HCQ initiation until 10 days after HCQ initiation.

Clinical outcomes

Our primary clinical outcome was improvement in hypoxia between the day of HCQ initiation and 10 days after HCQ initiation. Hypoxia was graded at baseline, day 5, and day 10 using criteria of the Sequential Organ Failure Assessment (SOFA) Score (S1 Table and S2 Table; [22, 23]). If an arterial blood gas was obtained, we used the lowest partial pressure of oxygen (mm Hg)/fraction of inspired oxygen (PaO2/FIO2) ratio on the day of assessment. Otherwise, the lowest peripheral capillary oxygen saturation (SpO2)/FIO2 ratio was used. Improvement in the SOFA hypoxia score or discharge between baseline and day 10 after HCQ initiation was considered an improvement in hypoxia; whereas, a worsening score or death was considered worsening of hypoxia.

Secondary outcomes included the need for invasive mechanical ventilation within 10 days after HCQ initiation among patients who were not receiving mechanical ventilation at the start of HCQ therapy. Among patients who had fever (temperature ≥38.0°C) on the day of HCQ initiation, we assessed the proportion of patients who became afebrile for at least 48 hours within the next 10 days. We also assessed the proportion of patients who survived until hospital discharge and whether patients were discharged to home or to other facilities. The last day of study follow-up was June 19 2020.

Statistical analysis

Medians and interquartile ranges [IQR] were used to characterize continuous variables and percentages were used for categorical variables. We compared baseline variables between patients with and without improved SOFA hypoxia scores between baseline and 10 days after HCQ initiation, using Fisher’s exact or chi-squared tests for categorical variables and the Wilcoxon rank-sum test for continuous variables. A two-sided P value of ≤0.05 was used for statistical significance. Variables that were significantly associated with hypoxia improvement were entered into an initial multivariate logistic regression model. Variables were removed from this multivariate model in stepwise fashion until only variables with P<0.2 were retained in the final model. Adjusted odds ratios were calculated for each of these variables with 95% confidence intervals (CI). This method was also applied to identify variables that were independently associated with in-hospital mortality. Analyses were conducted using STATA, version 15.0 (StataCorp, College Station, TX).

Results

Baseline characteristics

A total of 153 hospitalized patients were treated with HCQ and included in the safety and tolerability cohort (Fig 1). Twelve of these patients were excluded from the clinical outcomes cohort because they also received remdesivir or were prescribed HCQ chronically. The median age of the overall cohort was 62 years (IQR 42–74), 63% were men, one-third were documented as white, and nearly one-third were of Hispanic ethnicity (Table 1). The most common comorbid illnesses were hypertension (50%), obesity (40%), chronic pulmonary disease (32%), and diabetes (24%).

Table 1

Baseline characteristics of 153 hospitalized patients with COVID-19 who were treated with hydroxychloroquine (HCQ).

Patient Characteristics	No. (% of total or IQR)
Demographics
Age	62 (47–74)
Female gender	56 (37)
Race
White	49 (32)
Asian	26 (17)
Black	12 (8)
Other	22 (14)
Not specified	32 (24)
Hispanic ethnicity	44 (29)
Comorbid illnesses
Hypertension	77 (50)
Obesity (BMI ≥30)	61 (40)
Pulmonary disease	49 (32)
Asthma	24 (16)
COPD	12 (8)
Obstructive sleep apnea	9 (6)
Diabetes	37 (24)
Coronary artery disease	28 (18)
Chronic kidney disease1	17 (11)
End-stage renal disease	6 (4)
Congestive heart failure	13 (9)
Cerebrovascular disease	11 (7)
Transplant recipient	8 (5)
Solid organ transplant	6 (4)
Bone marrow transplant	2 (1)
Active malignancy	10 (7)
Solid tumor	6 (4)
Hematologic malignancy	4 (3)
Rheumatologic disease	7 (5)
HIV infection	4 (3)
Social characteristics
Current smoker	5 (3)
Former smoker	35 (23)
Recent international travel	8 (5)
Known contact with SARS-CoV-2-infected patient	20 (13)
Healthcare worker	10 (7)
Residence at home prior to hospitalization	138 (90)
Presenting symptoms to hospital
Cough	128 (84)
Fever	116 (76)
Dyspnea	101 (66)
Myalgias	37 (24)
Diarrhea	36 (24)
Nausea or vomiting	30 (20)
Headache	22 (14)
Rhinorrhea	17 (11)
Sore throat	15 (10)
Status on day HCQ initiated
Days from hospitalization until HCQ initiation	1 (1–2)
Highest temperature (°C)	38.2 (37.2–38.8)
Fever (temperature ≥38.0°C)	89 (58)
Highest heart rate per minute	97 (84–107)
Highest respiratory rate per minute	22 (20–28)
Tachypnea (respiratory rate ≥22 per minute)	82 (54)
Lowest systolic blood pressure, mm Hg	103 (93–116)
Oxygen support
Ambient air	28 (18)
Low-flow oxygen2	69 (45)
Non-invasive mechanical ventilation or high-flow oxygen	2 (1)
Mechanical ventilation	49 (37)
PaO2/FIO2 ratio	150 (120–186)
Located in an intensive care unit	54 (35)
Laboratory parameters
White blood cell count, in 109 cells/L	6.1 (4.3–8.3)
Absolute lymphocyte count (ALC), in 109 cells/L	0.9 (0.6–1.2)
Lymphopenia (ALC <1x109 cells/L)	89 (58)
Hemoglobin, in g/dL	12.9 (11.7–14.3)
Platelet count, 109/L	182 (138–226)
Chest radiography findings
Bilateral infiltrates	94 (61)
Unilateral infiltrates	30 (20)
Pleural effusion	13 (9)
No infiltrate or effusion	18 (12)
QTc interval on electrocardiogram3	442 (420–462)
QTc interval ≥470 msec	20/117 (17%)
Antibacterial agents that were co-administered with HCQ4
Ceftriaxone	47 (31)
Azithromycin	27 (18)
Doxycycline	24 (16)

Variables are expressed as No. (%) or median (IQR), unless otherwise indicated.

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FIO2, fraction of inspired oxygen; HIV, human immunodeficiency virus; IQR, interquartile range; PaO2, partial pressure of oxygen (mm Hg); QTc interval, rate-corrected QT interval using Bazett’s formula [20]; SpO2, peripheral capillary oxygen saturation.

1Baseline serum creatinine ≥2 mg/dL.

2Includes oxygen via low-flow nasal cannula, face mask, or non-rebreather.

3117 patients had an electrocardiogram prior to initiation of HCQ.

4Included patients who received the antibacterial agent for ≥3 days and received part of this course at the same time as HCQ initiation.

HCQ was initiated a median of 1 day (IQR 1–2) after hospital admission. Ninety-three percent of patients received the recommended HCQ dosage of 600 mg twice daily for one day, followed by 400 mg daily. The majority of patients had fever and tachypnea on the day of HCQ initiation, 82% required supplemental oxygen, and 36% required invasive mechanical ventilation. The majority of patients had lymphopenia, but white blood cell, hemoglobin, and platelet counts were typically normal. Chest radiography demonstrated bilateral infiltrates in 61% of patients. An EKG was performed prior to HCQ initiation in 76% of patients and the median baseline QTc interval was 442 msec (IQR 420–462). Twenty-seven patients (18%) received ≥3 days of concurrent azithromycin therapy.

Forty-seven (40%) of the 117 patients who had a baseline EKG had a follow-up EKG between 1–10 days after HCQ initiation. The median increase in the QTc interval after the initiation of HCQ was 16 msec and 36% of patients had a QTc increase of ≥30 msec. Seven (15%) of these 47 patients had a QTc increase from <500 msec to ≥500 msec and all of these patients received additional medications that prolong the QT interval, including amiodarone (n = 3), azithromycin (n = 3), intravenous ondansetron (n = 3), and anti-psychotic medications (n = 2). Eight-six percent of patients were located on a telemetry unit after HCQ initiation. In total, 13 (9%) patients developed an incident arrhythmia between days 1–10 after HCQ initiation. One patient developed a non-sustained monomorphic ventricular tachycardia that lasted for 15 beats. This patient had a QTc increase from 435 msec to 467 msec after HCQ initiation and was receiving a continuous propofol infusion but did not receive another QT-prolonging medication. All other arrhythmias were supraventricular tachycardias. No patient developed torsades de pointes, although 9 (6%) died between day 1–10 after HCQ initiation after a do not resuscitate order was implemented and their heart rhythm was not assessed prior to death.

Fifteen percent of patients developed incident Grade 3 anemia and 10% developed incident Grade 3 lymphopenia within the 10 days after HCQ initiation (Table 2). Only 3 patients had a Grade 4 incident blood count abnormality. Grade 3 or 4 AST and ALT increases occurred in 11% and 9% of patients, respectively. Increases in alkaline phosphatase and total bilirubin were rare. Of the 147 patients who were not receiving renal replacement therapy prior to starting HCQ, 19 (13%) required renal replacement therapy within 10 days after HCQ initiation, and all but one of these patients also required vasopressors for hypotension.

Table 2

Incidence of grade 3 and 4 blood count and liver test adverse events within the first 10 days after initiating HCQ therapy in hospitalized patients with COVID-19.

Lab value	No. Evaluable1	Grade 3: No. (%)	Grade 4: No. (%)
Blood count abnormalities
Neutropenia2	136	3 (2.2%)	None
Lymphopenia3	125	13 (10.4%)	2 (1.6%)
Anemia4	134	20 (14.9%)	None
Thrombocytopenia5	138	None	1 (0.7%)
Liver test abnormalities
AST elevation6	122	10 (8.2%)	3 (2.5%)
ALT elevation6	123	8 (6.5%)	2 (1.6%)
Alkaline phosphatase elevation6	123	2 (1.6%)	None
Total bilirubin elevation7	123	4 (3.3%)	None

Grading scale based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase.

1Assessment for this adverse event was only evaluable in patients who: i) had a baseline laboratory value prior to HCQ initiation and between days 1–10 after initiating HCQ; and ii) did not have a laboratory value that corresponds to a Grade 3 or 4 adverse event on the day of HCQ initiation (blood counts only).

2Grades 3 and 4 neutropenia are defined as an absolute neutrophil count of 500–1000 and <500 (x109 cells/L), respectively.

3Grades 3 and 4 lymphopenia are defined as an absolute neutrophil count of 200–500 and <200 (x109 cells/L), respectively.

4Grade 3 anemia is defined as hemoglobin <8 g/dL or need for transfusion. Grade 4 anemia indicates life-threatening consequences where urgent intervention indicated.

5Grades 3 and 4 thrombocytopenia are defined as an absolute neutrophil count of 25–50 and <25 (x109/L), respectively.

6Grade 3 AST, ALT, and alkaline phosphatase elevations are defined as an increase >5–20 times the upper limit of normal (ULN) if baseline was normal or >5–20 times baseline if baseline was abnormal. Grade 4 AST and ALT elevations are defined as >20 times ULN if baseline was normal or >20 times baseline if baseline was abnormal.

7Grade 3 total bilirubin elevation is defined as an increase >3–10 times the upper limit of normal (ULN) if baseline was normal or >3–10 times baseline if baseline was abnormal. Grade 4 elevation is defined as >10 times ULN if baseline was normal or >10 times baseline if baseline was abnormal.

Eight-nine percent of patients completed their HCQ course and the median number of doses was 6 (IQR 4–6). The most common reasons that HCQ was prematurely discontinued were: clinical improvement leading to a decision that additional HCQ was unnecessary (n = 4), QTc prolongation (n = 3), death (n = 3), enrollment into a clinical trial that prohibited HCQ (n = 3), pre-existing thrombocytopenia (n = 2), pre-existing seizure and concern that HCQ might lower the seizure threshold (n = 1), and reason unknown (n = 1). Of 143 patients who did not have vomiting prior to HCQ initiation, 3 (2%) developed vomiting between 1–10 days after HCQ initiation. Of 121 patients who did not have diarrhea at baseline, 7 (6%) developed incident diarrhea.

Fifty-eight (41%) patients had improvement in their SOFA hypoxia score by day 5 and 73 (52%) had improvement by day 10 (Fig 2). By day 10, 28 (20%) had the same score, and 40 (28%) had a worse hypoxia score. Improvement in SOFA hypoxia score by day 10 occurred in 54% of patients who received HCQ without azithromycin and 41% of patients who received both HCQ and azithromycin (P = 0.2). Baseline factors associated with a lack of improvement in the hypoxia score by day 10 in univariate analysis were older age, use of outpatient non-steroidal anti-inflammatory drugs, tachypnea, hypotension, invasive mechanical ventilation, and lymphopenia (Table 3; S3 Table). In multivariate analysis, only age ≥65 (adjusted odds ratio [aOR] 0.43; 95% CI 0.20–0.90; P = 0.024) was associated with lack of improvement in hypoxia (Table 3). Concurrent treatment with ≥3 days of azithromycin was not associated with improvement in hypoxia in either univariate (OR 0.63; 95% CI: 0.27–1.49) or multivariate analysis (aOR 0.99; 95% CI: 0.38–2.60).

Fig 2

Sequential Organ Failure Assessment (SOFA) hypoxia scores (0: Least hypoxic; 4: Most hypoxic) at day 0 (day when HCQ initiated), and at days 5 and 10 after HCQ initiation among patients in the clinical outcomes cohort (S1 Table and S2 Table).

The number in each rectangle corresponds to the number of patients who had each score at each study timepoint. Discharge and deaths are reported as their own categories.

Table 3

Baseline factors associated with improvement in SOFA hypoxia score during the 10 days after treatment with HCQ.

	Univariate logistic regression		Multivariate logistic regression
Variable	Odds ratio (95% CI)	P	Adjusted odds ratio (95% CI)	P
Age ≥65 years	0.32 (0.16–0.64)	0.001	0.43 (0.20–0.90)	0.024
NSAID use as outpatient	0.41 (0.18–0.92)	0.03	Removed from final model1
Tachypnea (respiratory rate ≥22 breaths per min)	0.43 (0.22–0.84)	0.014	0.52 (0.24–1.12)	0.095
Hypotension (SBP ≤100 mm Hg)	0.36 (0.18–0.72)	0.004	0.48 (0.21–1.07)	0.072
Lymphopenia (<1x109 cells/μL)	0.49 (0.24–0.97)	0.04	0.47 (0.22–1.02)	0.056
Invasive mechanical ventilation	0.42 (0.21–0.86)	0.017	Removed from final model1
Azithromycin therapy2	0.63 (0.27–1.49)3	0.29	Removed from final model4

Abbreviation: NSAID, non-steroidal anti-inflammatory drug; SBP, systolic blood pressure.

1This variable was removed from the final multivariate model because its corresponding P value in the multivariate model was ≥0.2.

2Azithromycin used for ≥3 days and administered at the same time that HCQ was initiated.

3For comparison, the unadjusted odds ratio of SOFA hypoxia score improvement was 1.31 (95% CI 0.62–2.79) for ceftriaxone therapy and 1.03 (95% CI 0.41–2.60) for doxycycline therapy.

4In an alternate multivariate model where azithromycin therapy was retained (with older age, tachypnea, hypotension, and lymphopenia), the adjusted odds ratio for hypoxia improvement with azithromycin therapy was 0.99 (95% CI 0.38–2.60).

Of 89 patients who were not receiving mechanical ventilation on the day of HCQ initiation, 23 (26%) were intubated within 10 days after HCQ initiation and only one of these 23 were extubated during this time. Conversely, 12 (23%) of 52 patients who were receiving invasive mechanical ventilation at baseline were extubated within 10 days. Of 78 patients who had fever on the day of HCQ initiation, 62 (80%) became afebrile during the following 10 days, with a median time to defervescence of 3 days (IQR 2–5).

By the end of study follow-up, 21% of patients had died during their hospitalization, 77% had been discharged alive, and 2% were still hospitalized. None of the patients who were still hospitalized required supplemental oxygen. Of the patients discharged alive, 69% were discharged to home, 16% to a long-term care facility, 14% to an acute rehabilitation center, and 1% to inpatient hospice. The in-hospital mortality rate was 31% for patients who were receiving mechanical ventilation at the time of HCQ initiation, 18% for patients who were receiving supplemental oxygen but not requiring mechanical ventilation, and 8% for patients who were not requiring supplemental oxygen. Patients who received HCQ and azithromycin had a similar in-hospital mortality rate (22%) as those who received HCQ without azithromycin (21%). In a multivariate model, increasing age (aOR 1.06 per year increase; 95% CI: 1.03–1.10; P = 0.001) and leukocytosis (aOR 5.42; 95% CI: 1.88–15.63; P = 0.002) were independently associated with in-hospital mortality (Table 4). Concurrent azithromycin therapy was not associated with a reduction in-hospital mortality in either univariate (OR 1.07; 95% CI: 0.39–2.95) or multivariate analysis (aOR 1.14; 95% CI: 0.37–3.50; Table 4).

Table 4

Baseline factors associated with in-hospital mortality in patients treated with HCQ.

	Univariate logistic regression		Multivariate logistic regression
Variable	Odds ratio (95% CI)	P	Adjusted odds ratio (95% CI)	P
Age, per year increase	1.06 (1.03–1.10)	<0.001	1.06 (1.03–1.10)	0.001
Cerebrovascular disease	4.24 (1.13–15.78)	0.031	3.52 (0.79–15.64)	0.098
COPD	5.30 (1.49–18.13)	0.010	Removed from final model1
Invasive mechanical ventilation	2.38 (1.05–5.41)	0.038	Removed from final model1
Leukocytosis (white blood cell count > 10x109 cells/μL)	6.73 (2.53–17.90)	<0.001	5.42 (1.88–15.63)	0.002
Azithromycin therapy2	1.07 (0.39–2.95)3	0.79	Removed from final model4

Abbreviation: COPD, chronic obstructive pulmonary disease.

1This variable was removed from the final multivariate model because its corresponding P value in the multivariate model was ≥0.2.

2Azithromycin used for ≥3 days and administered at the same time that HCQ was initiated.

3For comparison, the unadjusted odds ratio of in-hospital mortality was 1.43 (95% CI 0.61–3.34) for ceftriaxone therapy and 0.91 (95% CI 0.28–2.97) for doxycycline therapy.

4In an alternate multivariate model where azithromycin therapy was retained (with older age, cerebrovascular disease, and leukocytosis), the adjusted odds ratio for in-hospital mortality with azithromycin therapy was 1.14 (95% CI 0.37–3.49).

Discussion

There are currently no proven effective therapies for COVID-19 that are available for widespread use. Although remdesivir showed promising preliminary results in one randomized trial [4], results from another trial were less favorable [24], this drug is not currently available for routine use, and it requires intravenous infusion. Thus, data on other potential therapies that are currently available are urgently needed. This report outlines the real-world experience of HCQ therapy for hospitalized patients with COVID-19 at two NYC hospitals. Although no control group was available to conclusively evaluate the efficacy of HCQ, we believe that our findings provide important information to clinicians who are assessing the risk/benefit profile of administering HCQ to acutely ill hospitalized patients with COVID-19.

We found that HCQ was reasonably safe and well-tolerated. Nearly 90% of patients were able to complete their HCQ course and the majority of discontinuations were not related to an adverse event. Incident nausea and vomiting were rare. Although incident Grade 3 or 4 lymphopenia, anemia, and AST elevations occurred in 10–15% of patients, abnormalities in these tests are common in patients with COVID-19 and in critically ill patients [25]. Fewer than 5% of patients developed neutropenia, thrombocytopenia, or elevations in alkaline phosphatase or total bilirubin. Similarly, although renal replacement therapy was required in 13% of patients, COVID-19 commonly causes acute kidney injury in critically ill patients, and almost all of these patients were hypotensive requiring vasopressor support [26, 27].

One major concern of HCQ use in acutely ill patients is the risk of torsades de pointes from QT prolongation [28]. Although supraventricular tachyarrhythmias occurred in nearly 10% of patients, no patient had a documented sustained ventricular tachyarrhythmia or torsades de pointes. However, the majority of patients in this study had an EKG at baseline to assess their QTc interval and three patients discontinued HCQ because of QTc prolongation. Furthermore, among patients with an EKG before and after initiating HCQ, more than one-third had a QTc interval increase of ≥30 msec. Thus, if HCQ is used for hospitalized patients with COVID-19, we believe that obtaining an EKG before and after initiating HCQ is a reasonable strategy to mitigate risk.

The efficacy of HCQ for hospitalized patients with COVID-19 is unknown. Interest in using HCQ for treating COVID-19 arose from its in vitro activity against SARS-CoV-2 and its favorable toxicity profile compared to chloroquine [6, 7]. This interest increased after the publication of a small non-randomized study that suggested potential increased virologic clearance of SARS-CoV-2 with the combination of HCQ and azithromycin [8]. This study has been widely criticized for its design [29, 30]. Subsequently, neither two small randomized trials of patients with mild-moderate COVID-19 [16, 31] nor two large observational studies of hospitalized patients identified a clinical benefit of HCQ for COVID-19 [9, 10]. However, results from large randomized trials are still needed to definitely evaluate the clinical efficacy of HCQ in hospitalized patients.

This study did not have a control group of patients who did not receive HCQ because these patients typically had mild disease and were quickly discharged, and thus did not serve as a reasonable comparator group. This lack of a control group precludes any firm conclusions about the efficacy of HCQ for hospitalized patients with COVID-19. However, only approximately one-half of patients had an improvement in their hypoxia within 10 days after initiating HCQ, while over one-quarter had worsening hypoxia or died. These data clarify that even if HCQ has clinical benefit, which remains uncertain, alternative therapies are desperately needed since a large proportion of patients do not improve with this treatment.

Another notable finding from this study is that patients who were treated with azithromycin and HCQ were not more likely to have improvements in hypoxia at 10 days and were not more likely to survive their hospitalization compared to those who were treated with HCQ only. The lack of additional benefit of azithromycin was identified in both univariate and multivariate analyses. Furthermore, the odds ratio of hypoxia improvement was numerically greater with other commonly used antibiotics used for pneumonia, ceftriaxone and doxycycline, than with azithromycin (Table 3). The number of patients who received concurrent HCQ and azithromycin and had baseline and follow-up EKGs was too small to conduct a meaningful analysis of the additional risk of QT prolongation. However, given that both agents prolong the QT interval [28], the lack of additional clinical benefit of azithromycin argues against routine addition of azithromycin to HCQ in hospitalized patients with COVID-19.

Our study has strengths and limitations. Among its strengths are detailed quantitative assessments of toxicity, tolerability, and clinical outcomes, and extended follow-up for the entire hospitalization in almost all patients. The limitations include an obvious lack of a control group that did not receive HCQ, as well as relying on data that were documented in the medical record. Thus, it is possible that the actual incidence of gastrointestinal adverse events was higher than what was recorded. However, our study team reviewed daily provider notes and our queries identified high interrater reliability for data collection, indicating that relevant data were consistently included in the medical record. Another notable limitation is that our findings cannot be extrapolated to patients who receive HCQ for mild disease or for prophylaxis.

Randomized clinical trials are needed to identify safe and effective treatments for COVID-19, including those that definitively delineate the incidence of adverse effects and efficacy of HCQ in hospitalized patients. In the meantime, we believe that these data add additional preliminary information on the potential risks and benefits of administering HCQ to hospitalized patients with COVID-19.

Classification of hypoxia according to Sequential Organ Failure Assessment (SOFA) score criteria1.

(DOCX)

Click here for additional data file.

Conversions of supplemental oxygen into FIO2 (fraction of inspired oxygen).

(DOCX)

Click here for additional data file.

(DOCX)

Click here for additional data file.

1 Jun 2020

PONE-D-20-13406

Safety, Tolerability, and Clinical Outcomes of Hydroxychloroquine for Hospitalized Patients with Coronavirus 2019 Disease

PLOS ONE

Dear Dr. Michael Satlin

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 16 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish

Academic Editor

PLOS ONE

Additional Editor Comments:

I have received the comments of the reviewers on your manuscript. Based on reviewer comments, your manuscript warrants publication in PLOS ONE, however, they would like you to revise your paper. Please see reviewer's comments and provide point by point response in your revised version.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include a copy of Table 3 which you refer to in your text on page 11.

3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information

4. Thank you for stating the following in the Acknowledgments Section of your manuscript:

'Funding: This work was partially supported by the National Center for Advancing Translational Science [UL1 TR002384 to Julianne Imperato-McGinley] at the National Institutes of Health'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

'The author(s) received no specific funding for this work.'

Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

If any authors received a salary from any of your funders, please state which authors and which funders.

If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a retrospective study on 153 hospitalized patients with COVID-19 who received HCQ. The manuscript is interesting and well written, though limited by an inherent retrospective design and heterogeneity of patients. The main finding is that HCQ is safe and, on average, well tolerated, even though its effectiveness cannot be determined (there is no control group).

-Were other HCQ dosages tested?

-"14% had a QTc increase from <500 msec to ≥500 msec." Did they have an underlying cardiac heart disease? Did they receive other QT-prolonging drugs or other cardiovascular drugs? What about the "One patient [who] developed a non-sustained monomorphic ventricular tachycardia"?

-"Of the 147 patients who were not receiving renal replacement therapy prior to starting HCQ, 19 (13%) required renal replacement therapy within 10 days after HCQ initiation". Were there other plausible causes (drugs, hypotension, septic shock, prior severe renal failure...) for renal function worsening?

-The prognostic role of comorbidities (cardiovascular, renal, respiratory, etc) should be investigated, particularly for deaths and mechanical ventilation. "9 (6%) died between day 1-10"; "Twenty-eight days after HCQ initiation, 19% of patients had died, 13% required mechanical ventilation"

Reviewer #2: This is a well-done study on the use of hydroxychlorochine in COVID patients Several reviews have been written on this field, however only few clinical data are available. This is the principal strength of this paper. Data clearly showed that this drug is well-tolerated and safe in these patients. However, as the Authors pointed out, in absence of a control group, it's impossible to know the clinical advantages of hydroxychlorochine. I suggests to mitigate in the discussion section positive sentences on clinical advantages of this treatment

Reviewer #3: The paper is clear answer for our doubt about the role of hydoxychlorqine in treatment of hospitalized Patients with Coronavirus 2019 and its suspected complications on the different systems of the patients with covid -19

Reviewer #4: In the present study the authors investigated safety, tolerability, and clinical outcomes of hydroxychloroquine (HCQ) for hospitalized patients with coronavirus 2019 disease. The authors concluded that HCQ appears to be reasonably safe and tolerable in most hospitalized patients with COVID-19. However, nearly one-half of patients did not improve with this treatment.

The manuscript is well written and easy to understand. The authors are expert in the field.

However, there are some major concerns and limitations which have to be to addressed:

- What was the exact dosage? 400 mg of HCQ daily for 5 days?

- The authors should re-analysis the findings when patients with HCQ and Azithromycin are excluded; they should show results on patients with only HCQ and HCQ plus Azithromycin. Are there significant differences in outcome?

- The authors should perform multivariate outcome analysis.

- As mentioned a control group that is not receiving HCQ is missing; please state more detailed in the section limitations.

- Please include an discuss the recent study (Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19, Geleris et al. NEJM, 05/2020)

- Did you observe a association between hydroxychloroquine use and intubation or death in your population?

- Given the lack of a randomized control group the interpretation of the results are difficult; conclusions made by the authors are difficult to transfer to clinical practice.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Luciano Agati, MD

Reviewer #3: Yes: Amal Bakry Abdul sattar

Reviewer #4: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

30 Jun 2020

Associate Editor:

1) Please include a copy of Table 3 which you refer to in your text on page 11.

Response: We apologize for this error. This was supposed to refer to Supplemental Table 4. We have changed Supplemental Table 4 to Table 3 to include it in the main body of the text.

2) Thank you for stating the following in the Acknowledgments Section of your manuscript:

'Funding: This work was partially supported by the National Center for Advancing Translational Science [UL1 TR002384 to Julianne Imperato-McGinley] at the National Institutes of Health'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

'The author(s) received no specific funding for this work.'

Response: We have removed the funding statement from the manuscript and revised the statement in the online submission form.

Reviewer #1:

1) This is a retrospective study on 153 hospitalized patients with COVID-19 who received HCQ. The manuscript is interesting and well written, though limited by an inherent retrospective design and heterogeneity of patients. The main finding is that HCQ is safe and, on average, well tolerated, even though its effectiveness cannot be determined (there is no control group).

Response: We thank the reviewer for their favorable comments about our manuscript.

2) Were other HCQ dosages tested?

Response: The vast majority of patients received the recommended dosage outlined in the Methods section. Thus, we were unable to assess other HCQ dosages. We added the following sentence to the Results section: “Ninety-three percent of patients received the recommended HCQ dosage of 600 mg twice daily for one day, followed by 400 mg daily” (lines 174-176, track changes version).

3) "14% had a QTc increase from <500 msec to ≥500 msec." Did they have an underlying cardiac heart disease? Did they receive other QT-prolonging drugs or other cardiovascular drugs? What about the "One patient [who] developed a non-sustained monomorphic ventricular tachycardia"?

Response: We modified this sentence to highlight that these patients received other QT-prolonging medications: “Seven (15%) of these 47 patients had a QTc increase from <500 msec to ≥500 msec and all of these patients received additional medications that prolong the QT interval, including amiodarone (n=3), azithromycin (n=3), intravenous ondansetron (n=3), and anti-psychotic medications (n=2; lines 186-190, track changes version). We also added the following sentence: This patient had a QTc increase from 435 msec to 467 msec after HCQ initiation and was receiving continuous propofol infusion but did not receive other QT-prolonging medications (lines 193-195, track changes version).

4) "Of the 147 patients who were not receiving renal replacement therapy prior to starting HCQ, 19 (13%) required renal replacement therapy within 10 days after HCQ initiation". Were there other plausible causes (drugs, hypotension, septic shock, prior severe renal failure...) for renal function worsening?

Response: Eighteen of the 19 patients who developed a requirement for renal replacement therapy were hypotensive and on vasopressors. We modified this sentence in the Results section to add: “… and all but one of these patients also required vasopressors for hypotension” (lines 204-205, track changes version).

5) The prognostic role of comorbidities (cardiovascular, renal, respiratory, etc) should be investigated, particularly for deaths and mechanical ventilation. "9 (6%) died between day 1-10"; "Twenty-eight days after HCQ initiation, 19% of patients had died, 13% required mechanical ventilation".

Response: Given that complete follow-up for the entire hospitalization is now available for 98% of the study cohort, we decided to remove the 28-day follow-up and instead characterize the outcome of in-hospital mortality. We constructed univariate and multivariate logistic regression models to assess factors associated with in-hospital mortality, including comorbidities. We revised the Methods section to indicate this change (lines 144-150, track changes version) and the Results section (lines 235-257, track changes version). We have now removed the original Figure 3 and replaced it with Table 4.

Reviewer #2:

1) This is a well-done study on the use of hydroxychloroquine in COVID patients. Several reviews have been written on this field, however only few clinical data are available. This is the principal strength of this paper. Data clearly showed that this drug is well-tolerated and safe in these patients. However, as the Authors pointed out, in absence of a control group, it's impossible to know the clinical advantages of hydroxychlorochine. I suggests to mitigate in the discussion section positive sentences on clinical advantages of this treatment

Response: We thank the reviewer for the favorable comments about our manuscript. We now note in the Discussion section recent studies that cast doubt as to the effectiveness of hydroxychloroquine (references 10, 11, 16; lines 292-295, track changes version).

Reviewer #3:

1) The paper is clear answer for our doubt about the role of hydoxychlorqine in treatment of hospitalized Patients with Coronavirus 2019 and its suspected complications on the different systems of the patients with covid -19.

Response: We thank the reviewer for their review of our manuscript.

Reviewer #4

1) In the present study the authors investigated safety, tolerability, and clinical outcomes of hydroxychloroquine (HCQ) for hospitalized patients with coronavirus 2019 disease. The authors concluded that HCQ appears to be reasonably safe and tolerable in most hospitalized patients with COVID-19. However, nearly one-half of patients did not improve with this treatment. The manuscript is well written and easy to understand. The authors are expert in the field. However, there are some major concerns and limitations which have to be to addressed:

Response: We thank the reviewer for their comments and thoughtful review of our manuscript.

2) What was the exact dosage? 400 mg of HCQ daily for 5 days

Response: The dosage of HCQ was 600 mg every 12 hours for 2 doses, followed by 400 mg daily for an additional 4 days. This is outlined in the Study Population section of Methods (lines 90-91, clean version).

3) The authors should re-analysis the findings when patients with HCQ and Azithromycin are excluded; they should show results on patients with only HCQ and HCQ plus Azithromycin. Are there significant differences in outcome?

Response: We thank the reviewer for this excellent suggestion. We added the following sentences to the Clinical Outcomes section of Results: ”Improvement in SOFA hypoxia score by day 10 occurred in 54% of patients who received HCQ without azithromycin and 41% of patients who received both HCQ and azithromycin (P=0.2)” and “Patients who received HCQ and azithromycin had a similar in-hospital mortality rate (22%) as those who received HCQ without azithromycin (21%)” (lines 219-221 and 250-251, track changes version). We also note these results in both univariate and multivariate logistic regression models in Tables 3 and 4 of the revised manuscript.

4) The authors should perform multivariate outcome analysis.

Response: Multivariate models for the outcomes of improvement in hypoxia score at day 10 and in-hospital mortality are now displayed in Tables 3 and 4 of the revised manuscript and are commented upon in the Results section.

5) As mentioned a control group that is not receiving HCQ is missing; please state more detailed in the section limitations.

Response: We outline in the Discussion the important limitation of the lack of a control group who did not receive HCQ in two different paragraphs (lines 298-301, track changes version and lines 327-328, track changes version).

6) Please include an discuss the recent study (Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19, Geleris et al. NEJM, 05/2020).

Response: We thank the reviewer for this suggestion and have added this reference, as well as references 11 and 16. We also added the following sentences to the Discussion section: “Subsequently, neither two small randomized trials of patients with mild-moderate disease [16, 31] nor two large observational studies of hospitalized patients identified a clinical benefit of HCQ for COVID-19 [9, 10]. However, results from large randomized trials are still needed to definitely evaluate the clinical efficacy of HCQ in hospitalized patients (lines 292-297, track changes version).

7) Did you observe a association between hydroxychloroquine use and intubation or death in your population?

Response: Our study did not have a control group of patients who did not receive hydroxychloroquine because essentially all hypoxic patients received hydroxychloroquine during the study period. Thus, we were unable to identify associations between hydroxychloroquine use and intubation or death.

8) Given the lack of a randomized control group the interpretation of the results are difficult; conclusions made by the authors are difficult to transfer to clinical practice.

Response: We agree with the reviewer’s noted limitation of our manuscript. However, we believe that these data provide clinicians with a detailed analysis of the safety, tolerability, and clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

15 Jul 2020

Safety, Tolerability, and Clinical Outcomes of Hydroxychloroquine for Hospitalized Patients with Coronavirus 2019 Disease

PONE-D-20-13406R1

Dear Dr. Satlin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Muhammad Adrish

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The Authors addressed all comments and improved the manuscript. I have no more questions / comments.

Reviewer #2: The Authors correctly reply to my suggestions, more recent articles on the same field were cited . I don't have further questions

Reviewer #4: The authors addressed all requests and comments. The present work might fulfill criteria for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: luciano agati, MD

Reviewer #4: No

16 Jul 2020

PONE-D-20-13406R1

Safety, Tolerability, and Clinical Outcomes of Hydroxychloroquine for Hospitalized Patients with Coronavirus 2019 Disease

Dear Dr. Satlin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Muhammad Adrish

Academic Editor

PLOS ONE