Adopté par plusieurs pays dans le monde contre la Covid-19, le protocole médical à base de cloroquine continue d’être défendu par de nombreux scientifiques.
Ayant été le premier à avoir expérimenté l’hydroxycloroquine et l’ayant publiquement défendu, Didier Raoult réagit, avec force, à chaque fois que l’efficacité de ce médicament contre le nouveau coronavirus est mise en doute.
Après la publication, le 22 mai, des conclusions d’une étude scientifique qui pointe l’inutilité, voire la nocivité, de cette solution thérapeutique, le célèbre professeur est ressorti de ses gonds. Il persiste et signe en clamant qu’il faut faire confiance aux résultats des vraies expériences sur des patients et non aux graphs de Big Data.
Sa conviction quant à la pertinence du protocole médical à base de cloroquine est partagé par de nombreux scientifiques dans le monde. Plus d’une centaine parmi ces derniers ont d’ailleurs publié une lettre ouverte pour dénoncer les conclusions, jugées infondées, publiées dans le Lancet.
Les scientifiques qui se rangent du côté du Pr. Raoult, dont une dizaine en France, se disent inquiets sur les méthodes de la vaste étude parue dans le magazine scientifique britannique, ayant conduit à la suspension d'essais cliniques sur l'hydroxychloroquine pour combattre la pandémie de coronavirus cliniquement appelé Covid-19.
Le retentissement de cette étude a "conduit de nombreux chercheurs à travers le monde à examiner minutieusement, en détail, la publication en question", écrivent les auteurs de la lettre.
"Cet examen a soulevé à la fois des inquiétudes liées à la méthodologie et à l'intégrité des données", soulignent-ils avant de faire une longue liste de points problématiques, du refus des auteurs de donner accès aux données à l'absence d'"examen éthique".
Notant que la médiatisation autour de cette étude a provoqué "une inquiétude considérable chez les patients et les participants" aux essais cliniques, ils appellent à la mise en place par l'Organisation mondiale de la Santé (OMS) ou une autre institution, "indépendante et respectée", d'un groupe chargé de mener une analyse indépendante des conclusions de l'étude.
Parmi les signataires de cette lettre ouverte se trouvent des cliniciens, des statisticiens et autres chercheurs du monde entier, de Harvard à l'Imperial College de Londres.
De quoi rassurer les nombreux patients, au Maroc, en Algérie, au Sénégal et dans d’autres pays qui prennent l"hydroxychloroquine contre l’infection de la Covid-19.
La lettre ouverte dénonciatrice
Open letter to MR Mehra, SS Desai, F Ruschitzka, and AN Patel, authors of"Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis”. Lancet. 2020 May 22:S0140-6736(20)31180-6. doi: 10.1016/S0140-6736(20)31180-6.
PMID: 32450107
and to Richard Horton (editor of The Lancet
.Concerns regardingthe statistical analysis and data integrityThe retrospective, observational study of 96,032 hospitalized COVID-19 patients from sixcontinents reported substantially increased mortality (~30% excessdeaths) and occurrence of cardiac arrhythmias associated with the use of the 4-aminoquinoline drugs hydroxychloroquine and chloroquine.
These results have had a considerable impact on public health practice and research. The WHO has pausedrecruitment to the hydroxychloroquine arm in their SOLIDARITY trial.
The UK regulatory body, MHRA,requested the temporarypausing of recruitment intoall hydroxychloroquine trials in the UK (treatment and prevention),
And France has changed its national recommendation for the use of hydroxychloroquine in COVID-19 treatmentand also halted trials.The subsequent media headlines have caused considerable concern to participants and patients enrolled in randomized controlled trials (RCTs) seeking to characterizethe potential benefits and risks of these drugsin the treatment and prevention ofCOVID-19 infections. There is uniform agreement that well conducted RCTs are needed to inform policies and practices.
This impact has led many researchers around the world to scrutinize in detail the publication in question. This scrutinyhas raised both methodological and data integrity concerns. The main concerns are listed as follows:
1.There wasinadequate adjustment for known and measured confounders (disease severity, temporal effects, site effects, dose used).
2.The authors have not adhered to standard practices in the machine learning and statistics community. They have not releasedtheir code or data. There is no data/code sharing and availability statement in the paper. The Lancet was among the many signatories on the Wellcome statementon data sharing for COVID-19 studies.
3.There was noethics review.
4.There was no mention of the countries or hospitals that contributed to the data sourceandno acknowledgments to their contributions.A request to the authors for information on the contributing centres was denied
.5.Data from Australia are not compatible with government reports (too many cases for just five hospitals, more in-hospital deaths than had occurred in the entire country during the study period). Surgisphere (the data company) have since statedthis was an error of classificationof one hospital from Asia.Thisindicates the need for further error checking throughout thedatabase.
6.Data from Africa indicate thatnearly 25% of all COVID-19 cases and 40% of all deaths in the continentoccurred in Surgisphere-associated hospitals which had sophisticated electronic patient data recording, and patient monitoring able to detect and record "nonsustained [at least 6 secs] or sustained ventricular tachycardia or ventricularfibrillation”. Both the numbers of cases and deaths, and the detailed data collection, seem unlikely.
7.Unusually small reported variances in baseline variables, interventions and outcomes between continents(Table S3).
8.Mean daily doses of hydroxychloroquine that are 100 mg higher than FDA recommendations, whereas 66% of the data are from North American hospitals.9.Implausible ratios of chloroquine to hydroxychloroquine use in some continents10.The tight 95% confidence intervals reported for the hazard ratios are unlikely.
For instance,for the Australiandata this would need about double the numbers of recorded deathsas were reported in the paper.The patient data have been obtained through electronic patient records and are held by the US company Surgisphere. In response to a request for the data Professor Mehra has replied; "Our data sharing agreements with the various governments, countries and hospitals do not allow us to share data unfortunately.
”Given the enormous importance and influence of these results, we believe it is imperative that:
1.The company Surgisphereprovides details on data provenance. At the very minimum, this means sharing theaggregated patient data at the hospital level (for all covariates and outcomes)
2.Independent validation of the analysis is performed by a group convened by the World Health Organization,or at least one other independent and respected institution. This would entail additional analyses (e.g. determining if there is a dose-effect)to assess the validity of the conclusions
3.There is openaccess to allthe data sharing agreements cited above to ensure that,in each jurisdiction,any mined data was legally and ethically collected and patient privacy aspects respectedIn the interests of transparency, we also ask The Lancet to make openly available the peer review comments that led to this manuscript to be accepted for publication.This open letteris signed by clinicians, medical researchers, statisticians, and ethicistsfrom across the world. The full list of signatoriesand affiliationscan be found below.
List of SignatoriesDr James Watson (Statistician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)1Professor Amanda Adler (Trialist & Clinician, Director of the Diabetes Trials Unit, UK)DrRavi Amaravadi (Researcher,University of Pennsylvania, USA)Dr Ambrose Agweyu (Medical researcher, KEMRI-Wellcome Trust Research Programme, Kenya)Professor MichaelAvidan(Clinician, Washington University in St Louis, USA)Professor Nicholas Anstey (Clinician, Menzies School of Health Research, Australia)Dr Yaseen Arabi (Clinician, King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia)Dr Elizabeth Ashley (Clinician, Director of the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Laos) Professor Kevin Baird (Researcher, Headof the Eijkman-Oxford Clinical Research Unit, Indonesia)Professor Francois Balloux (Researcher, Director of the UCL Genetics Institute, UK)Dr Clifford George Banda (Clinician, University of Cape Town, South Africa) Dr Edwine Barasa(Health economist, KEMRI-Wellcome Trust Research Programme, Kenya) Professor Karen Barnes (Clinical Pharmacology, University of Cape Town, South Africa)Professor David Boulware (Researcher& Triallist, University of Minnesota, USA)Professor Buddha Basnyat (Clinician, Head of the Oxford University Clinical Research Unit -Nepal, Nepal)Professor Philip Bejon (Medical researcher, Director of the KEMRI-Wellcome Trust Research Programme, Kenya)Professor Mohammad Asim Beg(Clinician/Researcher, Aga Khan University,Pakistan)Professor Emmanuel Bottieau (Clinician, Institute of Tropical Medicine, Antwerp, Belgium)Dr Sabine Braat (Statistician, University of Melbourne, Australia)Professor Frank Brunkhorst (Clinician, Jena University Hospital, Germany)Dr Todd Campbell Lee (Researcher, McGill University, Canada)Professor Caroline Buckee (Epidemiologist, Harvard TH Chan School of Public Health, USA)Dr James Callery (Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Professor John Carlin (Statistician, University of Melbourne & Murdoch Children’s Research Institute, Australia)Dr Nomathemba Chandiwana (Research Clinician, University of the Witwatersrand, South Africa)Dr Arjun Chandna (Clinician, Cambodia Oxford Medical Research Unit, Cambodia)Professor PhaikYeong Cheah (Ethicist/Pharmacist, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Professor Allen Cheng (Clinician, Monash University, Australia)Professor Leonid Churilov (Statistician, University of Melbourne, Australia)Professor Ben Cooper (Epidemiologist, University of Oxford, UK)Dr Cintia Cruz (PaediatricianMahidol Oxford Tropical Medicine Research Unit, Thailand)Professor Bart Currie (Director, HOT NORTH, Menzies School of Health Research, Australia)Professor Joshua Davis (Clinician, President of the Australasian Society for Infectious Diseases, Australia)Dr Jeremy Day (Clinician, Oxford University Clinical Research Unit, Vietnam)Professor Nicholas Day (Clinician,Director of the Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Hakim-Moulay Dehbi (Statistician, University College London, UK)Dr Justin Denholm (Clinician, Researcher, Ethicist, Doherty Institute, Australia)DrLennie Derde (Intensivist/Researcher, University Medical Center Utrecht, The Netherlands)Professor Keertan Dheda (Clinician/Researcher, University of Cape Town,& Groote Schuur Hospital, South Africa)Dr Mehul Dhorda (Clinical Researcher, Mahidol Oxford Tropical Medicine Research Unit, Thailand) Professor Annane Djillali (Dean of the School of Medicine,Simone Veil Université,France)Professor Arjen Dondorp (Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Joseph Doyle (Clinician, Monash University and Burnet Institute, Australia)Dr Anthony Etyang (Medical Researcher, KEMRI-Wellcome Trust Research Programme, Kenya)Dr Caterina Fanello (Epidemiologist, University of Oxford, UK)Professor Neil Ferguson (Epidemiologist, Imperial College London, UK)ProfessorAndrew Forbes (Statistician, Monash University, Melbourne, Australia)Professor Oumar Gaye (Clinical Researcher, University Cheikh Anta Diop, Senegal)Dr Ronald Geskus (Head of Statistics at theOxford University Clinical Research Unit, Vietnam)Professor Dave Glidden(Biostatistics, University of California, USA)Professor Azra Ghani (Epidemiologist, Imperial College London, UK)Prof Philippe Guerin (Medical researcher, University of Oxford, UK)Dr. Raph Hamers (Clinician/Trialist, Eijkman-OxfordClinical Research Unit, Indonesia)Professor Peter Horby (Clinical Researcher, Centre for Tropical Medicine and Global Health, University of Oxford)DrJens-Ulrik Jensen (Clinician/Trialist, University of Copenhagen, Denmark)Dr Hilary Johnstone (Clinical Research Physician, Independent)Professor Kevin Kain (Clinical Researcher, University of Toronto, Canada)Dr Sharon Kaur (Ethicist, University of Malaya, Malaysia)1For correspondence: james@tropmedres.ac Dr Evelyne Kestelyn (Head of Clinical Trials, Oxford University Clinical Research Unit, Vietnam)Dr Tan Le Van (Medical Researcher,Oxford University Clinical Research Unit, Vietnam)ProfessorKatherine Lee (Statistician, University of Melbourne, Australia)Professor Laurence Lovat (Clinical Director of Wellcome EPSRC Centre for Interventional & Surgical Sciences, UCL, UK)Professor Kathryn Maitland (Clinician, Imperial College London/KEMRI Wellcome Trust Programme, Kenya)Dr Julie Marsh (Statistician, Telethon Kids Institute, Australia)Professor John Marshall