Outside any therapeutic trial prescription of hydroxychloroquine for hospitalized patients with covid-19 during the first wave of the pandemic: A national inquiry of prescription patterns among French hospitalists.

INTRODUCTION: During the first wave of the coronavirus-disease 2019 (covid-19) pandemic in early 2020, hydroxychloroquine (HCQ) was widely prescribed in light of in vitro activity against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Our objective was to evaluate in early 2020 the rate of French hospitalists declaring having prescribed HCQ to treat covid-19 patients outside any therapeutic trial, compare the reasons and the determinants for having prescribed HCQ or not.
MATERIAL AND METHODS: A national inquiry submitted by email from May 7 to 25, 2020, to a sample of French hospitalists: doctors managing patients hospitalized for covid-19 in a French department of internal medicine or infectious diseases and identified in the directories of French hospitals or as a member of the French Infectious Diseases Society (SPILF). Primary outcome was the percentage of hospitalists declaring having prescribed HCQ to covid-19 patients. Secondary outcomes were reasons and determinants of HCQ prescription.
RESULTS: Among 400 (22.8%) responding hospitalists, 45.3% (95% CI, 40.4 to 50.1%) declared having prescribed HCQ to covid-19 patients. Two main profiles were discerned: HCQ prescribers who did not raise its efficacy as a motive, and non-prescribers who based their decision on evidence-based medicine. Multivariate analysis retained the following prescription determinants (adjusted odds ratio; 95% confidence interval): a departmental procedure for HCQ prescription (8.25; 4.79 to 14.20), having prescribed other treatments outside a therapeutic trial (3.21; 1.81 to 5.71), prior HCQ prescription (2.75; 1.5 to 5.03) and HCQ prescribed within the framework of a therapeutic trial (0.56; 0.33 to 0.95).
CONCLUSION: Almost half of the hospitalists prescribed HCQ. The physician's personality (questioning or not evidence-based-medicine principles in the context of the pandemic) and departmental therapeutic procedures were the main factors influencing HCQ prescription. Establishment of "therapeutic" procedures represents a potential means to improve the quality of therapeutic decision-making during a pandemic.

Introduction

By March 2021, the coronavirus-disease 2019 (covid-19) pandemic had affected more than 120 million persons worldwide and had led to more than 2.5 million deaths [1]. Despite the rapid initiation of numerous therapeutic trials [2], no antiviral treatment had proven efficacy in 2020 [3]. Chloroquine and hydroxychloroquine (HCQ) were the first drugs proposed to treat covid-19 in light of their in vitro activity against severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2) [4] that causes covid-19. HCQ has been used for decades to treat malaria and autoimmune diseases with a good safety profile and is inexpensive. At the start of 2020, the results of some studies suggested that HCQ might be effective against SARS-CoV-2 [5,6]. In the emergency context and without proof of its efficacy, HCQ was recommended in the national policies of many countries, notably emerging nations [7]. HCQ use was the object of numerous debates among caregivers and the public at large [8,9]. Results of physician surveys [10-12], analysis of HCQ prescriptions filled in city pharmacies [13-15] and observational in-hospital studies (S1 Table) showed that HCQ was widely prescribed worldwide during the first wave of the covid-19 pandemic in early 2020. However, no specific data on doctors’ reasons and determinants for prescribing HCQ in-hospital were available.

On 25 March 2020, French government authorized HCQ use only for hospitalized patients, after informed consent had been obtained and based on a collegial decision [16]. Because that authorization was in no way a recommendation, it remains to assess the attitudes and opinions of hospitalists.

The primary objective was to determine the percentage of internal medicine or infectious disease hospitalists declaring having started HCQ outside a therapeutic trial to manage covid-19 patients. Secondary aims were to analyze the reasons the hospitalists gave for having prescribed HCQ or not, and what determined that decision.

Materials and methods

Design of the study

Questionnaire

We built a questionnaire that was drafted, stored and available on Google Form© (S1-S3 Appendices). The first versions of the questionnaire were tested on departmental hospitalists (IM, LP, LA, JC, SD) to evaluate comprehension of the items and the time needed to complete the inquiry. The questionnaire consists of 68 questions: 25 were asked of all participants, 43 only to some according to their previous answers, with the total number varying from 37 to 62. A link to the electronic questionnaire was sent by e-mail starting May 1, 2020, with reminders sent at 1-week intervals, and closure May 25, 2020.

Participating hospitalists

The population targeted was defined as hospitalists managing covid-19 patients and practicing in France in a department of internal medicine or infectious disease, and entered in the directories of French hospitals (n = 1387) [17,18] or members of the French Infectious Diseases Society (SPILF) (n = 572). After the exclusion of 80 duplicates, the questionnaire was sent to 1879 hospitalists. Each participant provided written consent prior to gaining access to the questionnaire. Participants were not paid.

Declaration to the French Computer Watchdog Commission (CNIL)

The agreement of conformity of the study was obtained from the CNIL on April 20, 2020 (no. 2217633 v 0).

Statistical methods

The analysis considered two groups of hospitalists: one was composed of those who reported having started HCQ for a patient outside a clinical trial at least once (henceforth called prescribers); the other group (non-prescribers) included physicians who declared not having initiated HCQ, except within the framework of a therapeutic trial.

Continuous variables are reported as mean ± standard deviation (SD). Categorical variables are reported as number (percentages; which were calculated excluding missing data). Every relevant proportion is accompanied by its 2-sided 95% confidence interval (Wilson method). Missing data were not handled. A logistic-regression model assessed HCQ-prescription determinants. First, univariate analyses (p<0.2) selected potential explanatory variables that were then entered into the multivariate model (stepwise method with entry/stay significance levels of 0.2/0.05). The results are expressed as adjusted odd ratios (aOR) with their 95% confidence intervals. Due to the heterogeneity of the numbers of physicians per region (6 regions had <5% of the sample), to analyze the variable region in the logistic-regression model, the 13 metropolitan regions (exclusion of the three physicians from overseas departments) were grouped into five geographical areas: Île-de-France, Northeast (Bourgogne-Franche-Comté, Grand Est, Hauts-de-France), Northwest (Normandy, Brittany, Centre-Val de Loire, Pays de la Loire), Southwest (Nouvelle-Aquitaine, Occitanie) and Southeast (Auvergne-Rhône-Alpes, Provence-Alpes-Côte d’Azur, Corsica). Pearson’s correlation coefficient and its 95% confidence interval were used to assess the relationship between the HCQ-prescription rate and cumulative in-hospital–mortality rate per region. A p-value <0.05 was considered significant, unless specified otherwise. All statistical analyses were performed with SAS release 9.4 (SAS Institute Inc, Cary, NC) statistical software package.

Results

Among the 1879 to whom the questionnaire was sent, 127 were not received (distribution error message received after sending), 400 hospitalists completed the entire questionnaire, for a response rate of 22.8% (400/1752).

Responders’ characteristics

The demographic characteristics of the responders who completed the questionnaire are reported in Tables 1 and S2.

Table 1

Participating hospitalists’ characteristics.

	HCQ prescription for covid-19 patients
Characteristic	Total, n (%)	Yes, n (%)	No, n (%)
Sex
n	400	181	219
Male	208 (52)	87 (48.1)	121 (55.3)
Female	192 (48)	94 (51.9)	98 (44.7)
Years in practice, n
n	400	181	219
0–4	66 (16.5)	30 (16.6)	36 (16.4)
5–9	76 (19)	32 (17.7)	44 (20.1)
10–19	91 (22.8)	43 (23.8)	48 (21.9)
20–29	99 (24.8)	51 (28.2)	48 (21.9)
≥30	68 (17)	25 (13.8)	43 (19.6)
Hospital type
n	400	181	219
Private	22 (5.5)	12 (6.6)	10 (4.6)
Teaching public	210 (51.5)	89 (49.2)	121 (55.3)
Non-teaching public	168 (42)	80 (44.2)	88 (40.2)
Specialty
n	400	181	219
Other specialties	91 (22.8)	33 (18.2)	58 (26.5)
Infectious diseases (ID)	144 (36)	58 (32.0)	86 (39.3)
Internal medicine (IM)	137 (34.3)	73 (40.3)	64 (29.2)
ID & IM	28 (7)	17 (9.4)	11 (5.0)
Hospital region
n	400	181	219
Auvergne Rhône-Alpes	37 (9.3)	21 (11.6)	16 (7.3)
Bourgogne-Franche-Comté	24 (6.0)	15 (8.3)	9 (4.1)
Brittany	10 (2.5)	0 (0.0)	10 (4.6)
Centre-Val de Loire	16 (4.0)	6 (3.3)	10 (4.6)
Grand Est	58 (14.5)	19 (10.5)	39 (17.8)
Hauts-de-France	34 8.5)	7 (3.9)	27 (12.3)
Île-de-France	109 (27.3)	61 (33.7)	48 (21.9)
Normandy	20 (5.0)	14 (7.7)	6 (2.7)
Nouvelle-Aquitaine	24 (6.0)	10 (5.5)	14 (6.4)
Occitanie	18 (4.5)	7 (3.9)	11 (5.0)
Pays de la Loire	18 (4.5)	3 (1.7)	15 (6.8)
Provence-Alpes-Côte d’Azur & Corsica	29 (7.3)	17 (9.4)	12 (5.5)
Overseas departments	3 (0.8)	1 (0.6)	2 (0.9)
Previous HCQ prescription
n	398	181	217
No	89 (22.4)	28 (15.5)	61 (28.1)
Yes	309 (77.6)	153 (84.5)	156 (71.9)

HCQ was started to treat covid-19 by 45.3% of the hospitalists (95% CI, 40.4–50.1%); 93.6% (205/219) of the remaining responders never prescribed HCQ to their covid-19 patients, but 6.4% (14/219) sometimes continued HCQ prescribed by colleagues.

Physicians reasons for prescribing HCQ or not

Hospitalists’ most frequently chosen reasons for prescribing HCQ (Table 2) were the only therapeutic option available (no alternative; 56.9%), application of a collegial decision (50.8%), the favorable HCQ safety profile (49.7%), the potential severity of covid-19 (48.6%). About a third of the hospitalists recognized the uncertainty of HCQ efficacy, while only 13.8% declared having prescribed HCQ because “HCQ seemed effective”. For 10% (n = 19, 95% CI, 6.8 to 15.8%) of the responders, the prescription continued a third-party decision, the only reason for prescription was either “I applied a collegial decision” or “It was requested by the patients and/or his/her entourage” (n = 4).

Table 2

Physicians reasons for prescribing HCQ or not.

Reason	Hospitalists, n (%)	95% CI†
For prescription (multiple choice)	HCQ prescribers (N = 181)
Only therapeutic option available (no alternative)	103 (56.9)	49.6 to 63.9
You applied the recommendation of the collegial decision	92 (50.8)	43.6 to 58
It is an old drug with a known, favorable safety profile	90 (49.7)	42.5 to 56.9
Covid-19 is a potentially very serious disease	88 (48.6)	41.4 to 55.9
HCQ efficacy against covid-19 was not certain but usual rules for drugs are not applicable during a public health emergency	64 (35.4)	28.8 to 42.6
Its prescription was made possible by a health ministry decree	51 (28.2)	22.1 to 35.1
HCQ is an inexpensive and available drug	51 (28.2)	22.1 to 35.1
Requested by the patient or his/her entourage	37 (20.4)	15.2 to 26.9
HCQ seems to be effective against covid-19	25 (13.8)	9.5 to 19.6
It seemed difficult to resist media pressure	17 (9.4)	5.9 to 14.5
It was recommended by colleagues	13 (7.2)	4.2 to 11.9
It was recommended by “medical authorities”	10 (5.5)	3.0 to 9.9
Fear of medical–legal consequences	4 (2.2)	0.9 to 5.5
Fear of the how I would be viewed by my departmental colleagues	4 (2.2)	0.9 to 5.5
The patient had already taken HCQ for another indication	2 (1.1)	0.3 to 3.9
Not to prescribe HCQ (multiple choice)	HCQ non-prescribers (N = 219)
No indication according to currently available medicine/science data	163 (74.4)	68.3 to 79.8
Absence of official recommendation* supporting HCQ prescription	111 (50.7)	44.1 to 57.2
Fear of potential adverse events	79 (36.1)	30.3 to 42.6
You think it unethical to prescribe a non-validated drug outside therapeutic trials	78 (35.6)	29.6 to 42.2
None of your patients met the criteria for HCQ prescription established in your department	21 (9.6)	6.4 to 14.2
Fear that HCQ could contribute to covid-19 worsening	12 (5.5)	3.2 to 9.3
You are opposed to off-label prescription	10 (4.6)	2.5 to 8.2
No collegial organized discussion or in your department	9 (4.1)	2.2 to 7.6
You didn’t even consider its prescription	7 (3.2)	1.6 to 6.4
Fear of medical–legal consequences	5 (2.3)	1.0 to 5.2
Fear of the reactions or opinions of your colleagues	4 (1.8)	0.7 to 4.6
Refusal of the patient or his/her entourage	3 (1.4)	0.5 to 3.9

* Learned societies, the Academy of Medicine, National Association of Physicians.

† IC 95% values are percentages of respondents.

Overall, 84.5% (95% CI, 79.1 to 88.7%) of non-prescribers justified their choice by at least one of the following reasons (Table 2): “No indication according to the available medicine/science-based” (74.4%), “Consider it unethical to prescribe a drug that is not validated outside therapeutic trials” (35.6%), “opposed to off-label prescription” (4.6%) “No official recommendations supporting HCQ prescription” (50.7%). The remaining non-prescribers (15.5%) had practical reasons: no collegial discussion was organized in their department or patients did not meet the criteria for prescription. In addition, ~36% of non-prescribers feared potential adverse events of HCQ or covid-19 worsening under HCQ (5.5%).

Determinants of HCQ prescription

Univariate analyses identified factors associated with HCQ prescription (Tables 3 and S3). The most important was an established departmental procedure that increased HCQ prescriptions (8.36 [5.12 to 13.65]). That protocol indicated that HCQ should be prescribed to all (3%), certain (88%) or no patients (9%). Previous HCQ prescription, media pressure and the advice of colleagues also influenced HCQ prescription. Although 43.3% (95% CI, 38.5 to 48.1%) of the responders indicated that their HCQ prescription was influenced by the media pressure, that effect seemed somewhat variable: more prescriptions for 38.2% of the prescribers, fewer for 7.6% of them and 23.3% of non-prescribers. In contrast, no links were found between HCQ prescription and the intensity of the epidemic according to the region (S1 Fig, S4 Table), the physicians’ sex, the duration of his/her practicing medicine or the type of hospital (university or not).

Table 3

Univariate and multivariate analyses of HCQ-prescription determinants.

	Univariate analysis*		Multivariate analysis*
Determinant	aOR [95% CI]	P value	aOR [95% CI]	P value
Sex
Male	1
Female	0.75 [0.51 to 1.11]	0.1526
Years in practice, n
0–4	1
5–9	0.87 [0.45 to 1.7]	0.6882
10–19	1.08 [0.57 to 2.03]	0.8236
20–29	1.27 [0.68 to 2.38]	0.4458
≥30	0.7 [00.35–1.39]	0.3073
Specialty
Other specialty	1
Infectious diseases (ID)	1.19 [0.69 to 2.04]	0.5385
Internal medicine (IM)	2 [1.16 to 3.45]	0.0121
ID & IM	2.72 [1.14 to 6.49]	0.0245
Hospital type
Private	1
Teaching public	0.61 [0.25 to 1.48]	0.2771
Non-teaching public	0.76 [0.31 to 1.85]	0.5419
Hospital geographical region†
Paris region	1
Northwest	0.44[0.23 to 0.83]	0.0117
Northeast	0.43 [0.25 to 0.74]	0.0021
Southwest	0.54 [0.26 to 1.1]	0.0900
Southeast	1.07 [0.58 to 1.98]	0.8348
Previous HCQ prescription
No	1
Yes	2.14 [1.3 to 3.52]	0.0029	2.75 [1.5 to 5.03]	0.001
HCQ procedure
No	1
Yes	8.36 [5.12 to 13.65]	<0.001	8.25 [4.79 to 14.2]	< .0001
Outside a therapeutic trial prescription (others/HCQ)§
No	1
Yes	3.74 [2.3 to 6.07]	<0.001	3.21 [1.81 to 5.71]	< .0001
HCQ prescription in therapeutic trial
No	1
Yes	0.68 [0.45 to 1.03]	0.0707	0.56 [0.33 to 0.95]	0.0301
Other prescriptions in therapeutic trials
No	1
Yes	0.84 [0.56 to 1.28]	0.4242
Sensitive to media pressure
No	1
Yes	1.55 [1.04 to 2.32]	0.0301

*Univariate analyses (P<0.2) selected potential explanatory variables that were then tested in the multivariate model (stepwise method with entry/stay significance levels of 0.2/0.05). The results are expressed as adjusted odd ratios (aOR) [95% confidence interval (CI)].

†Northwest: Normandy, Brittany, Centre-Val de Loire and Pays de la Loire; Northeast: Bourgogne-Franche-Comté, Grand Est and Hauts-de-France, Southwest: Nouvelle-Aquitaine and Occitanie; Southeast: Auvergne-Rhône-Alpes, Provence-Alpes-Côte d’Azur and Corsica.

§Lopinavir/ritonavir, Remdesivir, interleukin (IL)-6 inhibitors and/or IL-1 inhibitors, convalescent plasma, corticosteroids or others.

The multivariable analysis retained the following criteria as being significantly and independently associated with HCQ prescription (Table 3): an established departmental HCQ-prescription procedure (aOR, 8.25, 95% CI, 4.79 to 14.2; P<0.0001), previously prescribed HCQ (aOR, 2.75, 95% CI, 1.5 to 5.03; P = 0.001), outside a therapeutic trial prescription of drugs other than HCQ to treat covid-19 (aOR, 3.21, 95% CI, 1.81 to 5.71; P<0.0001).

Discussion

This nationwide inquiry, conducted during the first wave of the covid-19 pandemic in France, addressing HCQ prescription, found that 45.3% of the responding hospitalists declared having prescribed HCQ to covid-19 patients outside any therapeutic trial. Two profiles could be discerned, distributed almost equally: prescribers, among whom only 13.8% based their decision on HCQ efficacy; and non-prescribers, among whom 85% relied on relevant evidence-based medicine (EBM) criteria to support their position. Our multivariate analysis retained the following as reasons being independently associated with prescribing HCQ: a departmental HCQ-prescription procedure, outside a therapeutic trial prescription of other treatments, prior HCQ prescription and no HCQ prescription within the framework of a therapeutic trial.

Percentage of HCQ prescribers

The observed prescriber rate (45.3%) was higher than in certain French (14%) [11] or international (12%) [19] inquiries, but lower than in others (90%) [12]. The differences can be explained by the specific prescription context (outpatient) [19], the country [12] or the time of the inquiries [19]. In the recurrent Sermo international inquiries, the mean prescriber rate was comparable to ours and varied over time: it increased from 33% to 58% from March to April 2020 (in-hospital or private practice), then declined from 66% to 28% from April to July (in-hospital practice exclusively) [10]. Those inquiries had methodological weaknesses: prescription context not always specified (in-hospital or private practice) [11], representativity of the responders unknown because of the selection method [10-12,19]. A high rate of HCQ prescription during the first wave of the pandemic has been associated by some authors with possible risks: toxicity [20-22], depletion of stocks [19,23] or deterring research [24,25]. Others suggest that HCQ may have been beneficial for patients hospitalized for Covid-19 (S1 Table). In any case, our study showed that French hospitalists were very divided on the prescription of HCQ during the first wave of covid-19 pandemic. This confirms the interest of an ethical reflection on the prescription of unproven interventions outside research in a pandemic period, such as that initiated by the WHO [26]. The examples against HCQ (unconfirmed efficacy as during Chikungunya virus infection) [3,27,28] and corticosteroids (efficacy discussed a priori [29], confirmed a posteriori) [30] illustrate the difficulty of this exercise.

The majority of prescribers seem to be aware that the effectiveness of HCQ has not been established: they used HCQ without citing efficacy as a criterion. They justifies their attitude by HCQ favorable tolerance profile or the disease severity, which are known prescription criteria, with others declared criteria: availability, price and regulatory context of HCQ prescription [31,32]. This attitude can evoke the prescription profile called “just do it” by Aquino and Cabrera in the context of the pandemic emergency, during which no specific treatment had proven efficacy [33]: prescribe treatments with unevaluated effects hoping for a favorable benefit/risk ratio but taking the risk of drugs being ineffective or even deleterious [34]. Furthermore, a clear majority (85%) of non-prescriber hospitalists explained their decisions citing relevant EBM criteria. A third of them declared they were afraid of potential adverse effects, seeming to adhere to the “first, do no harm” principle, even if that meant not prescribing a therapy that might later prove effective [33,34].

Our results confirmed that the HCQ-prescription rate differed according to the physician’s specialty [35] or geographical region [10,15,19] but not according to the number of years of experience, unlike Baicus et al and Mehta et al [28,36]. But this association was not retained by multivariate analysis, not performed in others studies [10,15,19,35,36]. That finding held true for the region and the specialty (internal medicine), probably partially because of the significant rate of internists who had previously prescribed HCQ before the covid-19 pandemic.

Among the determinants retained by the multivariate analysis, the existence of HCQ-prescription procedures was the factor the most strongly associated with HCQ prescription. Procedure existence per se could have incited hospitalists to prescribe HCQ. Moreover, departments that established procedures might have had more physicians favorable to HCQ use. The establishment of in-hospital procedures could enhance a sense of adequacy between healthcare practices and EBM [37,38]. No specific work on this question during a pandemic was found, other than a moderate-quality study of clinical guidelines published at the onset of the pandemic [39] and contribution of living guidelines [3].

The association between HCQ prescription in therapeutic trials and less HCQ prescription outside a therapeutic trial, as herein, could support the hypothesis that the HCQ prescription depends on the personality of the hospitalist: non prescribers are more likely to support EBM despite the pandemic context. But limiting that association to therapeutic trials on HCQ might simply illustrate that, for the departments that established therapeutic trials on HCQ, the hospitalists preferred including patients in trials rather than prescribe outside one. Moreover, the fact that HCQ prescribers declared prescribing, more often as non-prescribers, other treatments of non-proven efficacy against covid-19 indicates that their prescribing attitude is not specific to HCQ and to a more general tendency to prescribe treatments with unproven efficacy in times of pandemic, adopting a “just do it” profile [33,34]. Doctors experienced in using HCQ for another indication had more HCQ prescriptions for covid-19. Indeed, prior experience with a drug is a known factor for prescription [31]. This finding could reflect a cognitive bias [40].

While the link between poor-quality medical publications, media repercussions, and HCQ-prescription policies [8,13,15,35,41,42] or more HCQ prescriptions [13,15,35] has been reported, our multivariate analysis did not retain media pressure as being associated with increased HCQ prescription.

Strengths and limitations of this study

To our knowledge, no other study has evaluated the HCQ-prescription rate and reasons for its prescription during the pandemic of a well-characterized population of French internal medicine or infectious disease hospitalists. Moreover, responders estimated the mean overall quality of the questionnaire to be 7.2 (±1.2)/10.

The timing of the inquiry (May 2020) during the first wave of the covid-19 pandemic in France (February to May 2020) enabled assessment of HCQ prescription. This choice might also have biased certain responses. However, after the inclusion period no randomized trial results on a large population were available [43] and both French and World Health Organization (WHO) public health authority released recommendations toward HCQ use to treat covid-19 only within therapeutic trial [44,45].

Our study has several limitations. The response rate was only 22.8%, but nevertheless close to other inquiries on HCQ use during the pandemic: 17% (1215/7000) [12], 29% (785/2645) [36], or 27% (71/260) [46]. Our study was declarative, which could have partially impacted the results. Our inquiry was sent exclusively to internal medicine and infectious disease departments, so the findings cannot be extrapolated to other departments that could have prescribed HCQ, eg, geriatrics or intensive care.

Conclusions

This study provides information on in-hospital HCQ prescription outside any therapeutic trial in France during the first wave of the covid-19 pandemic: its high frequency, varied practices of the hospitalists according to each one’s questioning of EBM principles because of the pandemic, the influence of codified hospital procedures. Understanding the modalities of hospitalists’ therapeutic decision-making during the pandemic would be a first step towards subsequently optimizing therapeutic decision-making processes. The existence of prescription procedures was the factor the most strongly associated with HCQ prescription herein. Nonetheless, our findings suggest that prescription procedures during the pandemic is a way to improve the quality of therapeutic decisions. Notably, such protocols, elaborated by independent authorities, based on robust scientific data and up-dated according to validated procedures could help physicians provide better care of their patients.

Correlation between the in-hospital hydroxychloroquine prescription rate and cumulative in-hospital–mortality rate according to French geographic region during the first semester of 2020, ie, the first wave of covid-19.

(DOCX)

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Observational studies of off-label HCQ prescription for hospitalized covid-19 patients in real-life.

(DOCX)

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Comparison of participants’ specialties.

(DOCX)

Click here for additional data file.

HCQ-prescription determinants: Sources of information on HCQ to treat covid-19.

(DOCX)

Click here for additional data file.

Cumulative in-hospital–mortality rate per 100,000 inhabitants linked to covid-19 on May 7, 2020 in France.

(DOCX)

Click here for additional data file.

Inquiry questionnaire (French).

(DOCX)

Click here for additional data file.

Inquiry questionnaire (English).

(DOCX)

Click here for additional data file.

Checklist for Reporting Results of Internet E-Surveys (CHERRIES).

(DOCX)

Click here for additional data file.

(XLSX)

Click here for additional data file.

2 Nov 2021

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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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 manuscript is interesting because it reports original data concerning the prescription of hydroxychloroquine. So from the last method of results is interesting.

The discussion is too biased from my point of view, firstly there are many studies showing that off-label prescribing in French hospitals is up to 70% and therefore it is likely that the physicians who responded did not take this into account or do not really know what off-label drugs are, globally those off-label, that is, prescriptions not recognized by the "Agence Française du Médicament" do not necessarily correspond to what is recognized by the FDA, or those considered ineffective by the Cochrane Library The notion of off-label is at least as political a notion as it is scientific and country dependent.

The authors conclude that the unanimity made sure on the toxicity, and on the ineffectiveness of hydroxychloroquine, which is partisan and untrue. It does not really add value to this article and does not reflect the nature of the data in the literature

This part is therefore a partisan part for me and is too long and not linked to the study. The discussion should be limited to an evaluation of the answers and a reflection on the direction of answers, given the wording of the questions that are asked, this is a phenomenon usually observed in all surveys. Moreover, the notion of media pressure is a subjective notion and I suggest that this data be eliminated. In practice, this work is important, but the discussion reflects a partisan vision that profoundly reduces the value of the work, which should be concentrated on the observational part that is related to it.

Reviewer #2: This article is written well. However, I observed some discrepancies in the article. I would like to encourage authors to address the following points

1. Rewrite the abstract part in an organized manner

2. Study objective is not a part of the Method. Included this section in the introduction section

3. I found some general sentences and heading in the method section. That needs to be removed from there. They can be included in the introduction section (Declaration to the French 108 Computer Watchdog Commission (CNIL), Patient and public involvement)

4. Table 2 and Table 3 showed the 95% CI value. However, there are discrepancies between the range with their mean. Please reverify the calculation.

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Reviewer #1: No

Reviewer #2: Yes: Sujit Kumar Debnath

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9 Dec 2021

Colombes, France, December 9th, 2021

Dear Editor,

Please find on the PLOS ONE submission web site (https://www.editorialmanager.com/pone/) the revised version of our manuscript ID entitled, Off-label prescription of hydroxychloroquine for hospitalized patients with covid-19: a national inquiry of prescription patterns among French hospitalists, by A Bosquet, C Affo, L Plaisance, G Poenou, E Mortier and I Mahé. We took into account the requests of the PLOS ONE Academic Editor and reviewers 1 and 2.

Please find below the answers to each point raised by academic editor and reviewers.

1/Academic requirements

- Academic editor requirement 1. “Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.”

I made sure our manuscript meets PLOS ONE’s style requirements and modify for example heading and subheading styles or add a table (S4 table: line 608) to prevent a table from being in the legend of figure 1 in supporting information section.

- Academic editor requirements 2. “(…) Thank you for stating the following in the Competing Interests section:“Dr. Mahé reports grants from BMS Pfizer, grants from LEO Pharma, personal fees and non-financial support from BMS Pfizer, personal fees and non-financial support from Leo Pharma, personal fees and non-financial support from Bayer, outside the submitted work. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.”

Dr Mahé and I confirm that this does not alter our adherence to all PLOS ONE policies on sharing data and materials: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

2/ General comments from reviewers

- Comments 1 “(Is the manuscript technically sound, and do the data support the conclusions? Yes/yes”) and 2 (“Has the statistical analysis been performed appropriately and rigorously? (yes/yes”).

N/A

- Reviewers’ comment 3 (“Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1 answer: No”)

We agree to communicate the raw data of our work (answers from the 400 hospitalists who answered the questionnaire). The file name is: CovHYd Study (answers) Plos ONE_20211126_n400.

- Reviewers’ comment 4 (“Is the manuscript presented in an intelligible fashion and written in standard English? Yes/yes”).

N/A

3/ Additional comments from reviewer#1

“This manuscript is interesting because it reports original data concerning the prescription of hydroxychloroquine. So from the last method of results is interesting”

We thank the reviewers for their careful reading and their relevant and helpful comments.

“The discussion is too biased from my point of view, firstly there are many studies showing that off-label prescribing in French hospitals is up to 70% and therefore it is likely that the physicians who responded did not take this into account or do not really know what off-label drugs are, globally those off-label, that is, prescriptions not recognized by the "Agence Française du Médicament" do not necessarily correspond to what is recognized by the FDA, or those considered ineffective by the Cochrane Library The notion of off-label is at least as political a notion as it is scientific and country dependent.”

Thank you for this remark. Indeed, the term "off label prescription" used several times in the article is not the correct one. This is a translation error. We suggest replacing it generally with "outside a (or any) therapeutic trial" or in line 265 in marked copy manuscript with "unproven interventions outside of research", the term used in the WHO report (new reference 26).

“The authors conclude that the unanimity made sure on the toxicity, and on the ineffectiveness of hydroxychloroquine, which is partisan and untrue. It does not really add value to this article and does not reflect the nature of the data in the literature. This part is therefore a partisan part for me and is too long and not linked to the study. The discussion should be limited to an evaluation of the answers and a reflection on the direction of answers, given the wording of the questions that are asked, this is a phenomenon usually observed in all surveys.”

Indeed, the subject of the study is whether hospitalists prescribed HCQ and if yes or not, for what reasons during the first wave of the Covid-19 pandemic (when the benefit / risk ratio of HCQ was uncertain in this case). The aim of the study is not to know whether HCQ is effective, or not, in treating covid-19. We therefore propose to refocus the discussion on the answers given by the doctors and their significance. In addition, we have modified some formulations to be more neutral: for example,

- line 260 (marked copy manuscript) we wrote a high rate of HCQ prescription (…) has been associated by some authors with possible risk (insteed of … is associated with possible risk …),

- line 262, we have added “Others suggest that HCQ may have been beneficial for patients hospitalized for Covid-19 (S1 table)”,

- line 323, we have removed the sentence “Almost half of the hospitalists responding declared having prescribed HCQ without the efficacy of this molecule being recognized for the treatment of covid-19”

- line 353, we have removed the following words “ and is not without risk (29-31)”

- lines 368-370, we have removed the sentence “.In May 2020, studies, often retrospective and observational, going against HCQ use accumulated”

“Moreover, the notion of media pressure is a subjective notion and I suggest that this data be eliminated.”

Indeed, we completely agree that media pressure is a very subjective notion, that it is complex to analyze the responses that refer to it. We therefore propose to communicate the raw results concerning media pressure and to remove interpretations that could be risky. For example, we have removed the long discussion on media pressure, the HCQ prescription authorization policies and the prescription of HCQ (lines 381-402), the words “ways healthcare professionals can resist media pressure” (line 424), or “media pressure” (line 435 and 448) in the discussion section. In abstract, we propose to remove the sentence “Media pressure influenced HCQ prescription by 43.3% of the responders” (line 44-45) and the word “media pressure” (line 52).

“In practice, this work is important, but the discussion reflects a partisan vision that profoundly reduces the value of the work, which should be concentrated on the observational part that is related to it.”

As we indicated above, we have corrected the discussion to be closer to the answers of the hospitalists and revised some formulations to be more objective.

4/ Additional comments from reviewer #2

Reviewer #2: This article is written well. However, I observed some discrepancies in the article. I would like to encourage authors to address the following points

1. Rewrite the abstract part in an organized manner

We still completely agree with this remark and have followed the indications given on the following sites: https://journals.plos.org/plosone/s/submission-guidelines and https://plos.org/resource/how-to-write-a-great-abstract/.

2. Study objective is not a part of the Method. Included this section in the introduction section

We removed this section in the methods section and included it at the end of the introduction.

3. I found some general sentences and heading in the method section. That needs to be removed from there. They can be included in the introduction section (Declaration to the French 108 Computer Watchdog Commission (CNIL), Patient and public involvement)

We proposed to remove the sentence about patient and public involvement as they were not involved due to the pandemic context and the study protocol. On the other hand, we propose to keep the sentence concerning the declaration of the study to the French commission of the CNIL because it is a regulatory point of protection of people who answered the questionnaire of our study. This declaration is compulsory in France for this kind of study. It does not seem to us to have its place in the introduction according to the indications of the PLOS ONE submission guidelines site (introduction section: https://journals.plos.org/plosone/s/submission-guidelines).

4. Table 2 and Table 3 showed the 95% CI value. However, there are discrepancies between the range with their mean. Please reverify the calculation.

In table 2 (page 9), 95% IC values are percentages of respondents, not absolute numbers of respondents. We therefore propose to specify in a caption this "IC 95% values are percentages of respondents" in order to avoid any confusion (line 173). In Table 3, the values indicated are only odds ratios and their 95% IC. We do not believe there is any confounding factor. We checked the data of Table 3 for accuracy and found no errors. We therefore propose not to modify the original text.

To finish, changes to the discussion resulted in changes to the bibliography (46 references remaining instead of the initial 63). We have also made some additional changes:

- we find a mistake in bibliography (wrong reference 44 in Marked copy manuscript, line 589) and propose to correct it: “HCSP. SARS-CoV-2: therapeutic recommendations. Rapp HCSP. Paris: Haut Conseil de la Santé Publique; 2020 MarJun. Available: https://www.hcsp.fr/Explore.cgi/avisrapportsdomaine?clefr=801 https://www.hcsp.fr/Explore.cgi/AvisRapportsDomaine?clefr=847 »

- we have moved the discussion sub-chapter "strengths and weaknesses of this study" at the end of the discussion as is most often the custom.

We hope you will consider our paper for publication in Plos ONE, and we look forward to hearing from you.

Sincerely,

Antoine Bosquet, MD, for the authors

13 Dec 2021

Outside any therapeutic trial prescription of hydroxychloroquine for hospitalized patients with covid-19 during the first wave of the pandemic: a national inquiry of prescription patterns among French hospitalists

PONE-D-21-20849R1

Dear Dr. Antoine Bosquet,

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.

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Kind regards,

Abdelwahab Omri, Pharm B, Ph.D,

Academic Editor

PLOS ONE

22 Dec 2021

PONE-D-21-20849R1

Outside any therapeutic trial prescription of hydroxychloroquine for hospitalized patients with covid-19 during the first wave of the pandemic: a national inquiry of prescription patterns among French hospitalists

Dear Dr. Bosquet:

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. Abdelwahab Omri

Academic Editor

PLOS ONE