On meta-analytic models and the effect of hydroxychloroquine use in COVID-19

Pasquier, D., Nature Communications, doi:10.1038/s41467-025-60478-x, Jul 2025

Source

PDF

All
Studies

Meta
Analysis

https://c19hcq.org/pasquier.html

HCQ for COVID-19

1st treatment shown to reduce risk in March 2020, now with p < 0.00000000001 from 424 studies, used in 59 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,900+ studies for 172 treatments. c19hcq.org

Meta-analytic re-analysis of randomized COVID-19 trials (mortality in inpatients; hospitalization in outpatients) showing that hydroxychloroquine (HCQ) does not significantly increase inpatient mortality once Hartung-Knapp scale factors are constrained, and that the same correction shows a reduction in outpatient hospitalizations. Author demonstrates that the 11% mortality rise reported by Axfors et al. is driven by an artificially small Hartung-Knapp variance arising from a few tiny trials; truncating the scale factor yields a nonsignificant RR, similar to fixed-effect estimates. In outpatients, the adjustment narrows the CI, showing significantly lower hospitalization with HCQ, RR 0.77 [0.62-0.95].

9 meta analyses show significant improvements with hydroxychloroquine for mortality1-4, hospitalization1, recovery5, combined death/hospitalization/cases6, cases7,8, and viral clearance9.

Currently there are 38 HCQ for COVID-19 early treatment studies, showing 76% lower mortality [61‑85%], 67% lower ventilation [-710‑99%], 31% lower ICU admission [1‑53%], and 41% lower hospitalization [28‑51%].

Important missing comments or errors? Let us know.

1. Landsteiner de Sampaio Amêndola et al., COVID-19 Infection in Rheumatic Patients on Chronic Antimalarial Drugs: A Systematic Review and Meta-Analysis, Journal of Clinical Medicine, doi:10.3390/jcm11226865.mdpi.com, doi.org.

2. Risch, H., Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis, American Journal of Epidemiology, kwaa093, 27 May 2020, doi:10.1093/aje/kwaa093.oup.com, doi.org.

3. Risch (B), H., Response to: “Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients” and “Re: Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis”, American Journal of Epidemiology, July 20, 2020, doi:10.1093/aje/kwaa152.oup.com, doi.org.

4. Stricker et al., Hydroxychloroquine Pre-Exposure Prophylaxis for COVID-19 in Healthcare Workers from India: A Meta-Analysis, Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.001.sciencedirect.com, doi.org.

5. Prodromos et al., Hydroxychloroquine is effective, and consistently so used early, for Covid-19: A systematic review, New Microbes and New Infections, doi:10.1016/j.nmni.2020.100776.sciencedirect.com, doi.org.

6. Ladapo et al., Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis, medRxiv, doi:10.1101/2020.09.30.20204693.medrxiv.org, doi.org.

7. García-Albéniz et al., Systematic review and meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19, European Journal of Epidemiology, doi:10.1007/s10654-022-00891-4.springer.com, doi.org.

8. Han et al., The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis and clinical assessment: an updated meta-analysis of randomized trials, Journal of Thoracic Disease, doi:10.21037/jtd-23-1043.amegroups.com, doi.org.

9. Brouqui et al., SARS-CoV 2 Viral Clearance in 1276 Patients: Associated Factors and the Role of Treatment with Hydroxychloroquine and Azithromycin, Acta Scientific Microbiology, doi:10.31080/ASMI.2024.07.1413.actascientific.com, doi.org.

Pasquier et al., 11 Jul 2025, peer-reviewed, 1 author. Contact: pasquierdiego@gmail.com.

This Paper HCQ All

Abstract: Matters arising https://doi.org/10.1038/s41467-025-60478-x On meta-analytic models and the effect of hydroxychloroquine use in COVID-19 Received: 15 January 2024 Diego Pasquier Accepted: 19 May 2025 ARISING FROM C. Axfors et al. Nature Communications https://doi.org/10.1038/ s41467-021-22446-z (2021) 1234567890():,; 1234567890():,; Check for updates Hydroxychloroquine (HCQ) has been widely tested as a potential treatment in COVID-19. The largest randomized trial in hospitalized patients (the RECOVERY trial) found a numerically larger rate of allcause mortality in the HCQ arm compared with standard of care alone (RR, 1.09, 95% CI, 0.96 –1.23)1. These data clearly exclude a clinical beneﬁt and raise the question of a possible increased fatality rate caused by widespread HCQ use in the early phase of the pandemic. Since the RECOVERY trial was not powered to detect such ~10% increase in mortality, it is natural to pool the data with those of similar trials to obtain more precise estimates. The study of Axfors et al.2 is a high-quality systematic review that relevantly addresses this question and leads to the conclusion of a signiﬁcant increase of mortality associated with HCQ (OR, 1.11, 95% CI, 1.02 –1.20, p = 0.02). This is in contrast with other meta-analyses based on similar sets of trials, which reported wider conﬁdence intervals3–5. In a more recent meta-analysis, including more trials and with the ﬁnal Solidarity results, the trend was weaker6. This eleven percent increase in mortality is now being used to estimate the number of deaths caused by HCQ in various countries7. The shorter conﬁdence intervals reported in Axfors et al. originate mostly from the meta-analytic model used. Axfors et al. also included some extra unpublished studies, but these turned out to carry only 7.8% of the total weight, which cannot explain such tighter conﬁdence intervals. Here, we point out some difﬁculties related to the use of the Hartung–Knapp random-effect model in this dataset. First, the rationale for the Hartung–Knapp approach given by Axfors et al. is inconsistent with the nature of the adjustment. Second, the Hartung–Knapp adjustment may result in an effectively increased precision in certain cases8. This is a known problematic feature of the method (that can be ﬁxed in several ways). Some of the results reported here are a good example of a rather dramatic effect of the adjustment in real datasets. Finally, we conclude that there remains uncertainty regarding a potential adverse HCQ effect, in particular in light of the most recent meta-analysis. To further illustrate our point on the choice of model, we also discuss the case of HCQ effect on COVID-19 hospitalization in outpatients9. in order to provide more equality of weights between trials with moderate to large size (than, e.g., the DerSimonian–Laird approach)." This is a rather surprising justiﬁcation because, by construction, the weights in the two approaches are exactly the same, meaning that the point estimates of the meta-analyses always agree and only the conﬁdence intervals and p-values can differ. In either case the average effect is given by P wx ^ = Pi i i , μ i wi where xi is the estimate of study i and wi is its weight, given by the inverse of its variance, i.e. wi = 1=s2i . It is assumed that xi is normally distributed, i.e x i N ðμ, s2i Þ, with s2i = σ 2i + τ 2 , where σ 2i is the withinstudy sampling variance and τ2 is the between-study variance to..

DOI record: { "DOI": "10.1038/s41467-025-60478-x", "ISSN": [ "2041-1723" ], "URL": "http://dx.doi.org/10.1038/s41467-025-60478-x", "alternative-id": [ "60478" ], "article-number": "6353", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "15 January 2024" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "19 May 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "11 July 2025" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "The author declares no competing interests." } ], "author": [ { "ORCID": "https://orcid.org/0000-0002-5418-6379", "affiliation": [], "authenticated-orcid": false, "family": "Pasquier", "given": "Diego", "sequence": "first" } ], "container-title": "Nature Communications", "container-title-short": "Nat Commun", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2025, 7, 11 ] ], "date-time": "2025-07-11T09:03:45Z", "timestamp": 1752224625000 }, "deposited": { "date-parts": [ [ 2025, 7, 11 ] ], "date-time": "2025-07-11T09:03:47Z", "timestamp": 1752224627000 }, "indexed": { "date-parts": [ [ 2025, 7, 11 ] ], "date-time": "2025-07-11T09:40:05Z", "timestamp": 1752226805440, "version": "3.41.2" }, "is-referenced-by-count": 0, "issue": "1", "issued": { "date-parts": [ [ 2025, 7, 11 ] ] }, "journal-issue": { "issue": "1", "published-online": { "date-parts": [ [ 2025, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by-nc-nd/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 7, 11 ] ], "date-time": "2025-07-11T00:00:00Z", "timestamp": 1752192000000 } }, { "URL": "https://creativecommons.org/licenses/by-nc-nd/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 7, 11 ] ], "date-time": "2025-07-11T00:00:00Z", "timestamp": 1752192000000 } } ], "link": [ { "URL": "https://www.nature.com/articles/s41467-025-60478-x.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41467-025-60478-x", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41467-025-60478-x.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2025, 7, 11 ] ] }, "published-online": { "date-parts": [ [ 2025, 7, 11 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1056/NEJMoa2021436", "author": "RECOVERY collaborative group.", "doi-asserted-by": "crossref", "first-page": "881", "journal-title": "N. Engl. J. Med.", "key": "60478_CR1", "unstructured": "RECOVERY collaborative group. Hydroxychloroquine in hospitalized patients with Covid-19. N. Engl. J. Med. 384, 881–882 (2021).", "volume": "384", "year": "2021" }, { "author": "C Axfors", "journal-title": "Nat. Commun.", "key": "60478_CR2", "unstructured": "Axfors, C. et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat. Commun. 12, 2349 (2021).", "volume": "12", "year": "2021" }, { "DOI": "10.1056/NEJMoa2023184", "author": "WHO Solidarity trial Consortium.", "doi-asserted-by": "crossref", "first-page": "497", "journal-title": "N. Engl. J. Med.", "key": "60478_CR3", "unstructured": "WHO Solidarity trial Consortium. Repurposed antiviral drugs for Covid-19—Interim WHO solidarity trial results. N. Engl. J. Med. 384, 497–511 (2021).", "volume": "384", "year": "2021" }, { "DOI": "10.1002/14651858.CD013587.pub2", "doi-asserted-by": "crossref", "key": "60478_CR4", "unstructured": "Singh, B., Ryan, H., Kredo, T., Chaplin, M. & Fletcher, T. Chloroquine or hydroxychloroquine for prevention and treatment of COVID 19. Cochrane Database Syst. Rev. 2, CD013587 (2021)." }, { "DOI": "10.1080/20477724.2021.1936818", "author": "A Di Castelnuovo", "doi-asserted-by": "crossref", "first-page": "456", "journal-title": "Pathog. Glob. Health", "key": "60478_CR5", "unstructured": "Di Castelnuovo, A. et al. Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials. Pathog. Glob. Health 115, 456–466 (2021).", "volume": "115", "year": "2021" }, { "DOI": "10.1016/S0140-6736(22)00519-0", "author": "H Pan", "doi-asserted-by": "crossref", "first-page": "1941", "journal-title": "Lancet", "key": "60478_CR6", "unstructured": "Pan, H. et al. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet 399, 1941–1953 (2022).", "volume": "399", "year": "2022" }, { "DOI": "10.1016/j.biopha.2023.116055", "author": "A Pradelle", "doi-asserted-by": "crossref", "first-page": "116055", "journal-title": "Biomed. Pharmacother.", "key": "60478_CR7", "unstructured": "Pradelle, A. et al. Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate. Biomed. Pharmacother. 171, 116055 (2024).", "volume": "171", "year": "2024" }, { "DOI": "10.1002/sim.6879", "author": "A Wiksten", "doi-asserted-by": "crossref", "first-page": "2503", "journal-title": "Stat. Med.", "key": "60478_CR8", "unstructured": "Wiksten, A., Rücker, G. & Schwarzer, G. Hartung-Knapp method is not always conservative compared with fixed-effect meta-analysis. Stat. Med. 35, 2503–2515 (2016).", "volume": "35", "year": "2016" }, { "author": "À Avezum", "first-page": "100243", "journal-title": "Lancet Reg. Health Am.", "key": "60478_CR9", "unstructured": "Avezum, À. et al. Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE–Coalition V): a double-blind, multicentre, randomised, controlled trial. Lancet Reg. Health Am. 11, 100243 (2022).", "volume": "11", "year": "2022" }, { "DOI": "10.1002/sim.1009", "author": "J Hartung", "doi-asserted-by": "crossref", "first-page": "3875", "journal-title": "Stat. Med.", "key": "60478_CR10", "unstructured": "Hartung, J. & Knapp, G. A refined method for the meta-analysis of controlled clinical trials with binary outcome. Stat. Med. 20, 3875–3889 (2001).", "volume": "20", "year": "2001" }, { "DOI": "10.1002/sim.1262", "author": "K Sidik", "doi-asserted-by": "crossref", "first-page": "3153", "journal-title": "Stat. Med.", "key": "60478_CR11", "unstructured": "Sidik, K. & Jonkman, J. N. A simple confidence interval for meta-analysis. Stat. Med. 21, 3153–3159 (2002).", "volume": "21", "year": "2002" }, { "DOI": "10.1186/s12874-015-0091-1", "author": "C Röver", "doi-asserted-by": "crossref", "journal-title": "BMC Med. Res. Methodol.", "key": "60478_CR12", "unstructured": "Röver, C., Knapp, G. & Friede, T. Hartung-Knapp-Sidik-Jonkman approach and its modification for random-effects meta-analysis with few studies. BMC Med. Res. Methodol. 15, 99 (2015).", "volume": "15", "year": "2015" }, { "DOI": "10.1001/jama.2022.23257", "author": "S Florescu", "doi-asserted-by": "crossref", "first-page": "39", "journal-title": "JAMA", "key": "60478_CR13", "unstructured": "Florescu, S. et al. Long-term (180-day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial. JAMA 329, 39–51 (2023).", "volume": "329", "year": "2023" }, { "DOI": "10.18637/jss.v036.i03", "author": "W Viechtbauer", "doi-asserted-by": "crossref", "first-page": "1", "journal-title": "J. Stat. Softw.", "key": "60478_CR14", "unstructured": "Viechtbauer, W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 1–48 (2010).", "volume": "36", "year": "2010" } ], "reference-count": 14, "references-count": 14, "relation": {}, "resource": { "primary": { "URL": "https://www.nature.com/articles/s41467-025-60478-x" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "On meta-analytic models and the effect of hydroxychloroquine use in COVID-19", "type": "journal-article", "update-policy": "https://doi.org/10.1007/springer_crossmark_policy", "volume": "16" }

Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0