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All Studies   Meta Analysis    Recent:   

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 with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19hcq.org
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 studies1-93, including 5 missing RCTs13,19,48,56,57. 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 studies95-108, including 2 missing RCTs100,102. Four are in the appendix96,97,102,109 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The end of the inclusion period was almost a year out of date as of publication, which explains some of the missing studies.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.
8 meta analyses show significant improvements with hydroxychloroquine for mortality116-119, hospitalization116, recovery120, combined death/hospitalization/cases121, and cases122,123.
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: g.zhou@rug.nl.
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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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.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Systematic ' 'review.</jats:p></jats:sec><jats:sec><jats:title>Eligibility</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Data source</jats:title><jats:p>PubMed and ' 'Embase (1 January 2020–28 September 2022).</jats:p></jats:sec><jats:sec><jats:title>Risk of ' 'bias</jats:title><jats:p>Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies ' 'of Interventions tools were applied to assess the quality of ' 'studies.</jats:p></jats:sec><jats:sec><jats:title>Data ' 'analysis</jats:title><jats:p>Meta-analyses for each eligible drug were performed if ≥2 ' 'similar study designs were ' 'available.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In all, 65 ' '(25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, ' 'respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or ' 'angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, ' 'hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: ' '0.82 (95% CI 0.74 to 0.90), I<jats:sup>2</jats:sup>=48%), a result largely driven by one ' 'clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational ' 'studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the ' 'risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I<jats:sup>2</jats:sup>=96%) ' 'and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in ' 'reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate ' 'quality and of lower quality in observational ' 'studies.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Results ' 'from our analysis are insufficient to support an evidence-based repurposed drug policy for ' 'SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on ' 'repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable ' 'people are warranted to prevent the future waves of ' 'infection.</jats:p></jats:sec><jats:sec><jats:title>PROSPERO registration ' 'number</jats:title><jats:p>CRD42021292797.</jats:p></jats:sec>', 'DOI': '10.1136/bmjresp-2023-001674', 'type': 'journal-article', 'created': {'date-parts': [[2023, 8, 28]], 'date-time': '2023-08-28T16:50:35Z', 'timestamp': 1693241435000}, 'page': 'e001674', 'update-policy': 'http://dx.doi.org/10.1136/crossmarkpolicy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: ' 'systematic review and meta-analysis', 'prefix': '10.1136', 'volume': '10', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-1872-0084', 'authenticated-orcid': False, 'given': 'Guiling', 'family': 'Zhou', 'sequence': 'first', 'affiliation': []}, {'given': 'Stefan', 'family': 'Verweij', 'sequence': 'additional', 'affiliation': []}, {'given': 'Maarten J', 'family': 'Bijlsma', 'sequence': 'additional', 'affiliation': []}, {'given': 'Stijn', 'family': 'de Vos', 'sequence': 'additional', 'affiliation': []}, {'given': 'Katrien', 'family': 'Oude Rengerink', 'sequence': 'additional', 'affiliation': []}, { 'given': 'Anna Maria Gerdina', 'family': 'Pasmooij', 'sequence': 'additional', 'affiliation': []}, {'given': 'Debbie', 'family': 'van Baarle', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hubert G M', 'family': 'Niesters', 'sequence': 'additional', 'affiliation': []}, {'given': 'Peter', 'family': 'Mol', 'sequence': 'additional', 'affiliation': []}, {'given': 'Judith M', 'family': 'Vonk', 'sequence': 'additional', 'affiliation': []}, {'given': 'Eelko', 'family': 'Hak', 'sequence': 'additional', 'affiliation': []}], 'member': '239', 'published-online': {'date-parts': [[2023, 8, 28]]}, 'reference': [ { 'key': '2023082809501442000_10.1.e001674.1', 'unstructured': 'Johns Hopkins University CSSE COVID-19 data. 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Large scale clinical ' 'trials: lessons from the COVID-19 pandemic. BMJ Open Respir Res ' '2022;9:e001226. doi:10.1136/bmjresp-2022-001226', 'DOI': '10.1136/bmjresp-2022-001226'}, { 'key': '2023082809501442000_10.1.e001674.79', 'doi-asserted-by': 'crossref', 'unstructured': 'Griffith GJ , Morris TT , Tudball MJ , et al . Collider bias undermines ' 'our understanding of COVID-19 disease risk and severity. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ 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. FLCCC and WCH provide treatment protocols.
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