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Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis

Zhou et al., BMJ Open Respiratory Research, doi:10.1136/bmjresp-2023-001674, PROSPERO CRD42021292797
Aug 2023  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 421 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Meta analysis with many errors/limitations/biases, including many missing studies, use of unadjusted results, use of non-symptomatic results, and use of all-cause instead of COVID-19 hospitalization.
For HCQ, there are 93 missing studies Agarwal, Ahmed, Alegiani, Alqatari, Alzahrani, Arleo, Becetti, Belmont, Bhatt, Bhattacharya, Cassione, Chevalier, Chouhdari, Cordtz, Cordtz (B), Datta, de la Iglesia, Desbois, Dhibar, Dulcey, Erden, Ferri, Finkelstein, Fitzgerald, Fung, Gendebien, Gendelman, Gentry, Gianfrancesco, Goenka, Guillaume, Gönenli, Huang, Huang (B), Huh, Isnardi, Juneja, Jung, Kamstrup, Khoubnasabjafari, Khurana, Klebanov, Konig, Korkmaz, Küçükakkaş, Laplana, Liu, Llanos-Cuentas, Loucera, MacFadden, Macias, Mahto, Mathai, Mathew, McCullough, Naggie, Nasri, Obrișcă, Oku, Opdam, Oztas, Patel, Patil, Pham, Piñana, Polat, Raabe, Rabe, Rangel, Rao, Rentsch, Revollo, Sahebari, Salesi, Salvarani, Samajdar, Santos, Satti, Scirocco, Sen, Shahrin, Shaw, Shukla, Simova, Singer, Strangfeld, Sukumar, Trefond, Ugarte-Gil, Vivanco-Hidalgo, Yadav, Yadav (B), Zhong, including 5 missing RCTs Chouhdari, Dhibar, Llanos-Cuentas, Naggie, Nasri. Note that Dhibar is missing (1,168 patient PEP RCT with positive results, the smaller non-RCT Dhibar (B) is included).
For ivermectin, there are 14 missing studies Alam, Behera, Behera (B), Bernigaud, Carvallo, Chahla, Desort-Henin, Hellwig, IVERCOR PREP, Kerr, Mondal, Morgenstern, Samajdar (B), Tanioka, including 2 missing RCTs Chahla, Desort-Henin. Four are in the appendix Behera, Behera (B), Chahla, Morgenstern (B) but are not used in the analysis. For ivermectin, in contrast with HCQ, authors show only results for clinical trials. However, they do not include Chahla, an RCT.
All 4 ivermectin RCTs as of publication time show statistically significant efficacy (authors avoid showing this for Seet by not showing symptomatic cases).
Some of the included studies are very low quality and most of the missing studies are higher quality.
Authors sometimes use adjusted results but often use unadjusted results when adjusted results are available.
The end of the inclusion period was almost a year out of date as of publication, which explains some of the missing studies.
Other sample issues:
Uses unadjusted results for Tirupakuzhi Vijayaraghavan (adjusted results show improved efficacy).
Uses unadjusted results for Polo (adjusted results show improved efficacy).
Uses non-symptomatic results for Polo (symptomatic results show improved efficacy).
Uses non-symptomatic results for Seet (symptomatic results show improved efficacy).
Uses non-symptomatic results for Shabani (symptomatic results show improved efficacy).
Hospitalization results for Mitjà are missing (favors treatment).
Uses all-cause rather than COVID-19 hospitalization for Rajasingham.
We checked the data for only a small selection of entries, there may be additional issues.
Results for many pre-registered treatments are missing including nitazoxanide, favipiravir, bromhexine, colchicine, metformin, and povidone-iodine.
7 meta analyses show significant improvements with hydroxychloroquine for mortality Landsteiner de Sampaio Amêndola, Risch, Risch (B), Stricker, hospitalization Landsteiner de Sampaio Amêndola, recovery Prodromos, combined death/hospitalization/cases Ladapo, and cases García-Albéniz.
Currently there are 106 HCQ for COVID-19 pre-exposure prophylaxis studies, showing 30% lower mortality [14‑43%] and 28% fewer cases [20‑35%].
Zhou et al., 28 Aug 2023, peer-reviewed, 11 authors, trial PROSPERO CRD42021292797. Contact:
This PaperHCQAll
Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis
Guiling Zhou, Stefan Verweij, Maarten J Bijlsma, Stijn De Vos, Katrien Oude Rengerink, Anna Maria Gerdina Pasmooij, Debbie Van Baarle, Hubert G M Niesters, Peter Mol, Judith M Vonk, Eelko Hak
BMJ Open Respiratory Research, doi:10.1136/bmjresp-2023-001674
Objective Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults. Design Systematic review. Eligibility Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease.
Competing interests None declared. Patient consent for publication Not applicable. Provenance and peer review Not commissioned; externally peer reviewed. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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