Crunching the numbers. Responsibly.
Reliability concern: This paper was retracted on 2024-12-16. See notice: 10.1016/j.ijantimicag.2024.107416.
BACKGROUND: Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the effect of hydroxychloroquine on respiratory viral loads.
PATIENTS AND METHODS: French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point.
RESULTS: Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported in the litterature for untreated patients. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.
CONCLUSION: Despite its small sample size, our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
UNLABELLED: This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). Concerns have been raised regarding this article, the substance of which relate to the articles' adherence to Elsevier's publishing ethics policies and the appropriate conduct of research involving human participants, as well as concerns raised by three of the authors themselves regarding the article's methodology and conclusions. Elsevier's Research Integrity and Publishing Ethics Team, in collaboration with the journal's co-owner, the International Society of Antimicrobial Chemotherapy (ISAC), and with guidance from an impartial field expert acting in the role of an independent Publishing Ethics Advisor, Dr. Jim Gray, Consultant Microbiologist at the Birmingham Children's and Women's Hospitals, U.K., conducted an investigation and determined that the below points constituted cause for retraction: • The journal has been unable to confirm whether any of the patients for this study were accrued before ethical approval had been obtained. The ethical approval dates for this article are stated as being 5th and 6th of March 2020 (ANSM and CPP respectively), while the article states that recruitment began in “early March”. The 17th author, Prof. Philippe Brouqui, has confirmed that the start date for patient accrual was 6th March 2020. The journal has not been able to establish whether all patients could have entered into the study in time for the data to have been analysed and included in the manuscript prior to its submission on the 20th March 2020, nor whether all patients were enrolled in the study upon admission as opposed to having been hospitalised for some time before starting the treatment described in the article. Additionally, the journal has not been able to establish whether there was equipoise between the study patients and the control patients. • The journal has not been able to establish whether the subjects in this study should have provided informed consent to receive azithromycin as part of the study. The journal has concluded that that there is reasonable cause to conclude that azithromycin was not considered standard care at the time of the study. The 17th author, Prof. Philippe Brouqui has attested that azithromycin treatment was not, at the time of the study, an experimental treatment but a possible treatment for, or preventative measure against, bacterial superinfections of viral pneumonia as described in section 2.4 of the article, and as such the treatment should be categorised as standard care that would not require informed consent. This does not fully address the journal's concerns around the use of azithromycin in the study. In section 3.1 of the article, it is stated that six patients received azithromycin to prevent (rather than treat) bacterial superinfection. All of these were amongst the patients who also received hydroxychloroquine (HCQ). None of the control patients are reported to have received azithromycin. This would indicate that only patients in the HCQ arm received azithromycin, all of whom were in one center. The recommendations for use of macrolides in France at the time the study was conducted indicate that azithromycin would not have been a logical agent to use as first-line prophylaxis against pneumonia due to the frequency of macrolide resistance amongst bacteria such as pneumococci. These two points suggest that azithromycin would not have been standard practice across southern France at the time the study was conducted and would have required informed consent. • Three of the authors of this article, Dr. Johan Courjon, Prof. Valérie Giordanengo, and Dr. Stéphane Honoré have contacted the journal to assert their opinion that they have concerns regarding the presentation and interpretation of results in this article and have stated they no longer wish to see their names associated with the article. • Author Prof. Valérie Giordanengo informed the journal that while the PCR tests administered in Nice were interpreted according to the recommendations of the national reference center, it is believed that those carried out in Marseille were not conducted using the same technique or not interpreted according to the same recommendations, which in her opinion would have resulted in a bias in the analysis of the data. This raises concerns as to whether the study was partially conducted counter to national guidelines at that time. The 17th author, Prof. Philippe Brouqui has attested that the PCR methodology was explained in reference 17 of the article. However, the article referred to by reference 17 describes several diagnostic approaches that were used (one PCR targeting the envelope protein only; another targeting the spike protein; and three commercially produced systems by QuantiNova, Biofire, and FTD). This reference does not clarify how the results were interpreted. It has also been noted during investigation of these concerns that only 76% (19/25) of patients were viral culture positive, resulting in uncertainty in the interpretation of PCR reports as has been raised by Prof. Giordanengo. As part of the investigation, the corresponding author was contacted and asked to provide an explanation for the above concerns. No response has been received within the deadline provided by the journal. Responses were received by the 3rd and 17th authors, Prof. Philippe Parola and Prof. Philippe Brouqui, respectively, and were reviewed as part of the investigation. These two authors, in addition to 1st author Dr. Philippe Gautret, 13th author Prof. Philippe Colson, and 15th author Prof. Bernard La Scola, disagreed with the retraction and dispute the grounds for it. Having followed due process and concluded the aforementioned investigation and based on the recommendation of Dr. Jim Gray acting in his capacity as independent Publishing Ethics Advisor, the co-owners of the journal (Elsevier and ISAC) have therefore taken the decision to retract the article.
Strengths
The study addressed one of the most urgent clinical questions of early 2020 and named its target population, decision context, and application mechanism explicitly. The research question itself was legitimate and well-motivated by prior in vitro and early clinical evidence.
↳ Introduction
The paper reports daily nasopharyngeal PCR data against a pre-specified primary endpoint of virological clearance at day 6, with the comparison presented in legible tables. This makes the claimed comparison transparent to a reader.
↳ Outcome; Table 2
The discussion explicitly identifies decision-makers and frames the findings as relevant to immediate pandemic action, articulating a clear, if unsupported, pathway to use. This gives the work high traction on the dimension of real-world relevance.
↳ Discussion, final paragraphs
Limitations
Treated patients were sampled daily while most controls were sampled every other day and imputed as positive on missing days. Because viral clearance is time-dependent, this systematically inflates the apparent clearance advantage of the treatment group.
↳ Table 2 footnote
Six of 26 treated patients (23%), including three ICU transfers and one death, were dropped from the analyzed cohort while controls had zero dropout. This informative per-protocol censoring, with no intention-to-treat analysis, biases the result toward apparent efficacy.
↳ Results, Demographics and Clinical Presentation
The article was retracted by Elsevier and ISAC following an investigation citing possible pre-approval accrual, unresolved informed-consent questions for azithromycin, cross-site PCR inconsistency, and three co-authors disavowing the methodology and conclusions. These concerns could materially change interpretation of the core findings.
↳ Retraction notice
Withdrawn — shown for reference only
The adjudicated scores are driven by a cluster of systematic biases that all inflate the apparent treatment effect: controls sampled every other day and imputed as positive (Table 2 footnote), per-protocol exclusion of the six sickest treated patients with zero control dropout (Results), and an unadjusted ~14-year age gap with severity imbalance (Table 1). Against these design failures, the abstract's associative framing gives way to causal language and a direct treatment recommendation in the discussion, a claim-evidence mismatch that constrains Contribution and Reporting. Evaluations converged strongly on Contribution, Positioning, and the merit of Methodological Rigour; the main divergence was how much credit the presence of standard statistical tests deserves when those tests do not address confounding, missingness, or site effects, and the execution-focused reading prevailed. On impact, the paper's explicit naming of decision-makers supports high traction, but the retraction and the failure of subsequent randomized trials to replicate any benefit limit its translation, transferability, and trajectory.
Very Limited1.7/5.0
The research question was timely and clinically urgent, but the claimed advance (clinical efficacy supporting a direct treatment recommendation) is disproportionate to a non-randomized open-label study of 20 analyzed patients. The contribution is primarily temporal rather than methodological.
we recommend that COVID-19 patients be treated with hydroxychloroquine and azithromycin
Multiple systematic biases compromise the primary comparison: controls were sampled every other day and imputed as positive while treated patients were sampled daily, the sickest treated patients were excluded per-protocol, and a ~14-year age gap went unadjusted. The merit-based score of 1.5 sits below the 2.0 Red-reliability cap, so the cap is not triggered.
control patients from centers other than Marseille did not undergo daily sampling, but were sampled every other day
The manuscript is structurally readable with legible tables and a clear population-intervention-outcome statement, but qualifying language shifts from associative in the abstract to causal claims and a treatment recommendation in the discussion. Ambiguity about which patients populate each analysis set further reduces precision.
our first results are so significant and evident
The paper engages adequately with the in vitro and Chinese chloroquine literature, but the limitations section is perfunctory, omitting the non-random dropout, baseline imbalance, differential sampling, and the QT-prolongation safety debate. No reporting standard is referenced.
a small sample size, limited long-term outcome follow-up, and dropout of six patients
Concerns4 of 4 checks
The primary virological comparison is compromised by differential sampling between arms (controls sampled every other day and imputed as positive in the Table 2 footnote), unadjusted baseline imbalance in age and disease severity (Table 1), and per-protocol exclusion of 6 of 26 treated patients including the sickest who were transferred to ICU or died (Results). The Abstract and Discussion advance causal efficacy claims and a direct treatment recommendation that exceed what a non-randomized N=36 design can support.
The article was formally retracted by Elsevier and ISAC following an investigation. Documented concerns include whether patients were accrued before ethical approval (approval dated 5-6 March vs. recruitment in 'early March'), whether informed consent was required for azithromycin (judged likely not standard care), cross-site PCR methodology inconsistency, and three co-authors requesting removal of their names over the methodology and conclusions.
Flags: 2 declared / 5 total
All 31 cited references resolved to real publications via PubMed, Crossref, or OpenAlex.
This paper was retracted on 2024-12-16. See notice: 10.1016/j.ijantimicag.2024.107416.
Sources: Retraction Watch ✓PubPeer (coming soon)
Low2.3/5.0
The paper directly addresses an urgent real-world problem and explicitly names decision-makers and an international strategy, giving it a clear and visible application pathway. Relevance reflects the claimed relevance and named stakeholders, not the reliability of the evidence.
open the possibility of an international strategy to decision-makers
Findings are an early, small, open-label observational signal that the paper frames as deployment-ready, but the design cannot support implementation. The evidence does not reach pilot-validated or operationally tested status.
The small, single-center-dominated sample, cross-site differences in sampling and PCR handling, and absence of sensitivity analyses limit generalizability. The findings were not replicated in subsequent trials.
The paper connected to an active early-pandemic evidence base but is a weak and contested building block, given the retraction and the subsequent randomized trials that found no benefit. Its cumulative-progress value is limited but not entirely absent.
Lower confidence on Trajectory — domain match limited.
Nabu’s assessment, alongside the field’s view.
Evaluation Metadata
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