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All Studies   Meta Analysis       

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial

Schilling et al., PLOS Medicine, doi:10.1371/journal.pmed.1004428, COPCOV, NCT04303507
Sep 2024  
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Symp. case, PCR+ COVI.. 57% Improvement Relative Risk Symp. case, PCR+ resp. i.. 39% Symp. case, post-hoc p.. 15% post-hoc primary Work days lost 23% Severe adverse events 46% Meta analysis PCR+ sy.. 42% Meta analysis (post-hoc) p.. 20% HCQ  COPCOV  Prophylaxis  DB RCT Is pre-exposure prophylaxis with HCQ beneficial for COVID-19? Double-blind RCT 4,652 patients in multiple countries (Apr 2020 - Mar 2022) Fewer symptomatic cases with HCQ (p=0.00024) c19hcq.org Schilling et al., PLOS Medicine, September 2024 FavorsHCQ Favorscontrol 0 0.5 1 1.5 2+
HCQ for COVID-19
1st treatment shown to reduce risk in March 2020, now with p < 0.00000000001 from 419 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 109 treatments. c19hcq.org
RCT 4,652 low-risk participants, published 820 days days after completion, showing significantly lower PCR+ COVID-19 cases with HCQ/CQ prophylaxis, p = 0.0004.
Authors include a meta-analysis of this and 11 other RCTs confirming significantly lower COVID-19 cases.
Authors conclude that HCQ/CQ could have been deployed with benefit early in the pandemic.
HCQ/CQ was well tolerated with no serious drug-related adverse events. There were significantly fewer severe adverse events with treatment. (Serious adverse events refer to serious outcomes while severe adverse events refer to intensity, e.g., severe headache).
Authors note that "the primary outcome was subsequently changed to include seroconversion" rather than only PCR+ cases. The date of this change is not reported. The PCR+ results are the most reliable. Inclusion of seroconversion means that participants with asymptomatic COVID-19 and symptomatic non-COVID-19 infections will be counted as symptomatic COVID-19 cases. Supplementary Table A8 confirms that there were many non-COVID-19 infections. The progressively less accurate serum serology and DBS serology dilute the results as shown in Table 2. False negative results at day 0 will result in additional false positive outcomes according to the post-hoc algorithm - false negatives may be especially frequent with DBS. 70% of participants were seropositive at baseline - Given the high false negative rate of serum/DBS serology, false negative baseline serology may account for many/most of the seroconversion cases.
Further, the reported primary outcome including serology does not match the earlier specified seroconversion analysis.
Two post-hoc SAPs are dated April 26, 20221 and December 10, 20222. The second version makes key changes to the algorithm. In the April version, cases where PCR was done and PCR was negative were considered negative, however the December version allows PCR negative cases to be considered positive COVID-19 cases based on serum/DBS. Further, for DBS the April version requires an increase within the window matching symptoms and flu negative, while the December version only requires an increase between D0 and D90.
We are not aware of a reason for these changes other than to reduce the efficacy shown in that outcome.
The December 10 changes were long after the results would normally have been published during a pandemic killing millions of people - it is inconceivable that authors did not know the results at that time, and inconceivable that the 57% lower symptomatic PCR+ cases was not reported very soon after trial completion.
The protocol states that details for interim analyses were clearly detailed in the SAP, however the available SAP versions do not mention interim analyses.
Reporting is biased. For example authors' interpretation is that "HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs", without mentioning the large statistically significant reductions in PCR+ symptomatic cases both in this RCT and the meta analysis.
1,299 patients received HCQ and 1,021 received CQ. Authors do not provide results for HCQ alone.
Health related quality of life results are not reported.
Preliminary analysis, please report errors.
risk of symptomatic case, 56.9% lower, RR 0.43, p < 0.001, treatment 24 of 2,320 (1.0%), control 56 of 2,332 (2.4%), NNT 73, PCR confirmed COVID-19.
risk of symptomatic case, 39.4% lower, RR 0.61, p = 0.009, treatment 44 of 2,320 (1.9%), control 73 of 2,332 (3.1%), NNT 81, PCR confirmed respiratory infections.
risk of symptomatic case, 15.1% lower, RR 0.85, p = 0.05, treatment 240 of 2,320 (10.3%), control 284 of 2,332 (12.2%), NNT 55, post-hoc primary outcome.
risk of miscellaneous, 23.5% lower, RR 0.77, p < 0.001, treatment 700 of 181,263 (0.4%), control 932 of 184,688 (0.5%), NNT 844, work days lost.
severe adverse events, 46.3% lower, RR 0.54, p = 0.005, treatment 31 of 2,320 (1.3%), control 58 of 2,332 (2.5%), NNT 87, severe adverse events.
risk of miscellaneous, 42.0% lower, RR 0.58, p < 0.001.
risk of miscellaneous, 20.0% lower, RR 0.80, p < 0.001, meta analysis of (post-hoc in some cases) primary outcomes.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Schilling et al., 12 Sep 2024, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, median age 29.0, 88 authors, study period 29 April, 2020 - 10 March, 2022, trial NCT04303507 (history) (COPCOV). Contact: william@tropmedres.ac.
This PaperHCQAll
Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial
William H K Schilling, Mavuto Mukaka, James J Callery, Martin J Llewelyn, Cintia V Cruz, Mehul Dhorda, Thatsanun Ngernseng, Naomi Waithira, Maneerat Ekkapongpisit, James A Watson, Arjun Chandna, Erni J Nelwan, Raph L Hamers, Anthony Etyang, Mohammad Asim Beg, Samba Sow, William Yavo, Aurel Constant Allabi, Buddha Basnyat, Sanjib Kumar Sharma, Modupe Amofa-Sekyi, Paul Yonga, Amanda Adler, Prayoon Yuentrakul, Tanya Cope, Janjira Thaipadungpanit, Panuvit Rienpradub, Mallika Imwong, Mohammad Yazid Abdad, Stuart D Blacksell, Joel Tarning, Frejus Faustin Goudjo, Ange D Dossou, Abibatou Konaté-Touré, Serge-Brice Assi, Kra Ouffoué, Nasronudin Nasronudin, Brian Eka Rachman, Pradana Zaky Romadhon, Didi Darmahadi Dewanto, Made Oka Heryana, Theresia Novi, Ayodhia Pitaloka Pasaribu, Mutiara Mutiara, Miranda Putri Rahayu Nasution, Khairunnisa Khairunnisa, Fauzan Azima Dalimunthe, Eka Airlangga, Akmal Fahrezzy, Yanri Subronto, Nur Rahmi Ananda, Mutia Rahardjani, Atika Rimainar, Ruth Khadembu Lucinde, Molline Timbwa, Otieno Edwin Onyango, Clara Agutu, Samuel Akech, Mainga Hamaluba, Jairus Kipyego, Obadiah Ngachi, Fadima Cheick Haidara, Oumar Y Traoré, François Diarra, Basudha Khanal, Piyush Dahal, Suchita Shrestha, Samita Rijal, Youssouf Kabore, Eric Adehossi, Ousmane Guindo, Farah Naz Qamar, Abdul Momin Kazi, Charles J Woodrow, Steven Laird, Maina Cheeba, Helen Ayles, Phaik Yeong Cheah, Walter R J Taylor, Elizabeth M Batty, Kesinee Chotivanich, Sasithon Pukrittayakamee, Weerapong Phumratanaprapin, Lorenz Von Seidlein, Arjen Dondorp, Nicholas P J Day, Nicholas J White
PLOS Medicine, doi:10.1371/journal.pmed.1004428
Background Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use.
Supporting information S1 A1 . List of COPCOV study sites. Table A2 . Baseline characteristics in the COPCOV trial (Per Protocol Analysis). Table A3 . Outcomes of Chloroquine/Hydroxychloroquine and Placebo Pre-exposure Prophylaxis against COVID-19 in the COPCOV study (Per Protocol Analysis). Table A4 . Summary of Serious Adverse Events in the COPCOV study. Table A5 . Primary and secondary outcomes of Chloroquine/Hydroxychloroquine Therapy for Pre-exposure Prophylaxis against COVID-19 (missing outcomes treated as not having had COVID-19 during the study period) ITT-Results presented as "Risk differences." Table A6 . Outcomes of Chloroquine/Hydroxychloroquine and Placebo Pre-exposure Prophylaxis against COVID-19 in the COPCOV study (removing cases for which the SEAC judged that a study endpoint could not be determined). Table A7 . Summary characteristics of previously published pre-exposure prophylaxis studies considered for meta-analysis. Table A8 . Listing of causes of PCR-confirmed respiratory illness. Author Contributions Conceptualization: William H. K. Schilling, Arjun Chandna, Arjen Dondorp, Nicholas P. J. Day, Nicholas J. White. Data curation: William H. K. Schilling, Mavuto Mukaka, Thatsanun Ngernseng, Naomi Waithira, James A. Watson, Otieno Edwin Onyango, Elizabeth M. Batty.
References
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{ 'indexed': {'date-parts': [[2024, 9, 13]], 'date-time': '2024-09-13T00:51:06Z', 'timestamp': 1726188666752}, 'reference-count': 33, 'publisher': 'Public Library of Science (PLoS)', 'issue': '9', 'license': [ { 'start': { 'date-parts': [[2024, 9, 12]], 'date-time': '2024-09-12T00:00:00Z', 'timestamp': 1726099200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}], 'funder': [ { 'DOI': '10.13039/100010269', 'name': 'Wellcome Trust', 'doi-asserted-by': 'publisher', 'award': ['221307/Z/20/Z'], 'id': [{'id': '10.13039/100010269', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}], 'content-domain': {'domain': ['www.plosmedicine.org'], 'crossmark-restriction': False}, 'abstract': '<jats:sec id="sec001">\n' '<jats:title>Background</jats:title>\n' '<jats:p>Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised ' 'with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and ' 'efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did ' 'not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest ' 'clinical benefit, guidelines recommend against its use.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec002">\n' '<jats:title>Methods and findings</jats:title>\n' '<jats:p>Healthy adult participants from the healthcare setting, and later from the community, ' 'were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised ' 'trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine ' '(CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint ' 'was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up ' 'period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe ' 'Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 ' 'symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 ' 'infection); participant reported number of workdays lost; genetic and baseline biochemical ' 'markers associated with symptomatic COVID-19, respiratory illness and disease severity (not ' 'reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality ' 'of life measures (not reported here).</jats:p>\n' '<jats:p>The primary and safety analyses were conducted in the intention-to-treat (ITT) ' 'population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned ' 'but was not possible because of protracted delays resulting from controversies over efficacy ' 'and adverse events with HCQ use, vaccine rollout in some countries, and other factors. ' 'Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled ' '(HCQ/CQ <jats:italic>n</jats:italic> = 2,320; placebo <jats:italic>n</jats:italic> = 2,332). ' 'The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and ' 'asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of ' 'symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ' 'ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; <jats:italic>p</jats:italic> = ' '0.05]).</jats:p>\n' '<jats:p>For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred ' 'in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to ' '1.12; <jats:italic>p</jats:italic> = 0.6). There were no differences in the severity of ' 'symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated ' 'with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 ' '(95% CI, 0.42 to 0.88; <jats:italic>p</jats:italic> = 0.009) and fewer days lost to work ' 'because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; ' '<jats:italic>p</jats:italic> &lt; 0.001). The prespecified meta-analysis of all published ' 'pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit ' 'against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated ' 'with no drug-related serious adverse events (SAEs). Study limitations include the smaller ' 'than planned study size, the relatively low number of PCR-confirmed infections, and the lower ' 'comparative accuracy of serology endpoints (in particular, the adapted dried blood spot ' 'method) compared to the PCR endpoint. The COPCOV trial was registered with <jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="http://clinicaltrials.gov/" ' 'xlink:type="simple">ClinicalTrials.gov</jats:ext-link>; number <jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://clinicaltrials.gov/ct2/show/NCT04303507" ' 'xlink:type="simple">NCT04303507</jats:ext-link>.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec003">\n' '<jats:title>Interpretation</jats:title>\n' '<jats:p>In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe ' 'and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective ' 'benefit in a meta-analysis including this trial and similar RCTs.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec004">\n' '<jats:title>Trial registration</jats:title>\n' '<jats:p>ClinicalTrials.gov <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ' 'ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT04303507" ' 'xlink:type="simple">NCT04303507</jats:ext-link>; ISRCTN Registry <jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://www.isrctn.com/ISRCTN10207947" ' 'xlink:type="simple">ISRCTN10207947</jats:ext-link>.</jats:p>\n' '</jats:sec>', 'DOI': '10.1371/journal.pmed.1004428', 'type': 'journal-article', 'created': {'date-parts': [[2024, 9, 12]], 'date-time': '2024-09-12T17:40:12Z', 'timestamp': 1726162812000}, 'page': 'e1004428', 'update-policy': 'http://dx.doi.org/10.1371/journal.pmed.corrections_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A ' 'double-blind, randomised, placebo-controlled trial', 'prefix': '10.1371', 'volume': '21', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-6328-8748', 'authenticated-orcid': True, 'given': 'William H. 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'family': 'Cheeba', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-4108-2842', 'authenticated-orcid': True, 'given': 'Helen', 'family': 'Ayles', 'sequence': 'additional', 'affiliation': []}, {'given': 'Phaik Yeong', 'family': 'Cheah', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-6236-0464', 'authenticated-orcid': True, 'given': 'Walter R. J.', 'family': 'Taylor', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-8559-452X', 'authenticated-orcid': True, 'given': 'Elizabeth M.', 'family': 'Batty', 'sequence': 'additional', 'affiliation': []}, {'given': 'Kesinee', 'family': 'Chotivanich', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sasithon', 'family': 'Pukrittayakamee', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-5896-1961', 'authenticated-orcid': True, 'given': 'Weerapong', 'family': 'Phumratanaprapin', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-0282-6469', 'authenticated-orcid': True, 'given': 'Lorenz', 'family': 'von Seidlein', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-5190-2395', 'authenticated-orcid': True, 'given': 'Arjen', 'family': 'Dondorp', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nicholas P. J.', 'family': 'Day', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-1897-1978', 'authenticated-orcid': True, 'given': 'Nicholas J.', 'family': 'White', 'sequence': 'additional', 'affiliation': []}, { 'name': 'on behalf of the COPCOV Collaborative Group', 'sequence': 'additional', 'affiliation': []}], 'member': '340', 'published-online': {'date-parts': [[2024, 9, 12]]}, 'reference': [ { 'key': 'pmed.1004428.ref001', 'unstructured': 'World Health Organization WHO Coronavirus (COVID-19) Dashboard. ' 'Available from: https://covid19.who.int/. Last accessed 2023 Oct 25.'}, { 'key': 'pmed.1004428.ref002', 'doi-asserted-by': 'crossref', 'first-page': '69', 'DOI': '10.1186/1743-422X-2-69', 'article-title': 'Chloroquine is a potent inhibitor of SARS coronavirus infection and ' 'spread.', 'volume': '2', 'author': 'MJ Vincent', 'year': '2005', 'journal-title': 'Virol J.'}, { 'key': 'pmed.1004428.ref003', 'doi-asserted-by': 'crossref', 'first-page': '269', 'DOI': '10.1038/s41422-020-0282-0', 'article-title': 'Remdesivir and chloroquine effectively inhibit the recently emerged ' 'novel coronavirus (2019-nCoV) in vitro.', 'volume': '30', 'author': 'M Wang', 'year': '2020', 'journal-title': 'Cell Res'}, { 'key': 'pmed.1004428.ref004', 'doi-asserted-by': 'crossref', 'first-page': '160', 'DOI': '10.1038/d41586-020-01695-w', 'article-title': 'High-profile coronavirus retractions raise concerns about data ' 'oversight', 'volume': '582', 'author': 'H Ledford', 'year': '2020', 'journal-title': 'Nature'}, { 'issue': '21', 'key': 'pmed.1004428.ref005', 'doi-asserted-by': 'crossref', 'first-page': '2030', 'DOI': '10.1056/NEJMoa2022926', 'article-title': 'Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19', 'volume': '383', 'author': 'RECOVERY Collaborative Group', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'key': 'pmed.1004428.ref006', 'doi-asserted-by': 'crossref', 'first-page': '1257', 'DOI': '10.1080/14656566.2021.1898589', 'article-title': 'Does hydroxychloroquine still have any role in the COVID-19 pandemic?', 'volume': '22', 'author': 'WH Schilling', 'year': '2021', 'journal-title': 'Expert Opin Pharmacother'}, { 'key': 'pmed.1004428.ref007', 'article-title': 'Therapeutics and COVID-19.', 'author': 'World Health Organization'}, { 'issue': '10281', 'key': 'pmed.1004428.ref008', 'doi-asserted-by': 'crossref', 'first-page': '1262', 'DOI': '10.1016/S0140-6736(21)00469-4', 'article-title': 'Guidelines should not pool evidence from uncomplicated and severe ' 'COVID-19', 'volume': '397', 'author': 'NJ White', 'year': '2021', 'journal-title': 'Lancet'}, { 'key': 'pmed.1004428.ref009', 'article-title': 'India expands use of controversial drug for coronavirus despite safety ' 'concerns', 'author': 'P. Pulla', 'year': '2024', 'journal-title': 'Nature'}, { 'key': 'pmed.1004428.ref010', 'doi-asserted-by': 'crossref', 'first-page': '517', 'DOI': '10.1056/NEJMoa2016638', 'article-title': 'A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis ' 'for Covid-19', 'volume': '383', 'author': 'DR Boulware', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'key': 'pmed.1004428.ref011', 'first-page': 'e20572', 'article-title': 'Pre-exposure Prophylaxis With Various Doses of Hydroxychloroquine Among ' 'Healthcare Personnel With High-Risk Exposure to COVID-19: A Randomized ' 'Controlled Trial.', 'volume': '13', 'author': 'F Syed', 'year': '2021', 'journal-title': 'Cureus'}, { 'key': 'pmed.1004428.ref012', 'doi-asserted-by': 'crossref', 'first-page': '195', 'DOI': '10.1001/jamainternmed.2020.6319', 'article-title': 'Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure ' 'SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical ' 'Trial.', 'volume': '181', 'author': 'BS Abella', 'year': '2021', 'journal-title': 'JAMA Intern Med'}, { 'issue': '5', 'key': 'pmed.1004428.ref013', 'doi-asserted-by': 'crossref', 'first-page': '417', 'DOI': '10.1056/NEJMoa2021801', 'article-title': 'A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of ' 'Covid-19', 'volume': '384', 'author': 'O Mitjà', 'year': '2021', 'journal-title': 'N Engl J Med'}, { 'key': 'pmed.1004428.ref014', 'doi-asserted-by': 'crossref', 'first-page': '808', 'DOI': '10.1186/s13063-021-05758-9', 'article-title': 'Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a ' 'double-blind, placebo-controlled randomized clinical trial.', 'volume': '22', 'author': 'B Grau-Pujol', 'year': '2021', 'journal-title': 'Trials'}, { 'key': 'pmed.1004428.ref015', 'doi-asserted-by': 'crossref', 'first-page': 'e835', 'DOI': '10.1093/cid/ciaa1571', 'article-title': 'Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease ' '2019 (COVID-19) in Healthcare Workers: A Randomized Trial.', 'volume': '72', 'author': 'R Rajasingham', 'year': '2021', 'journal-title': 'Clin Infect Dis'}, { 'key': 'pmed.1004428.ref016', 'doi-asserted-by': 'crossref', 'first-page': '314', 'DOI': '10.1016/j.ijid.2021.04.035', 'article-title': 'Positive impact of oral hydroxychloroquine and povidone-iodine throat ' 'spray for COVID-19 prophylaxis: An open-label randomized trial', 'volume': '106', 'author': 'RCS Seet', 'year': '2021', 'journal-title': 'Int J Infect Dis'}, { 'key': 'pmed.1004428.ref017', 'doi-asserted-by': 'crossref', 'first-page': '167', 'DOI': '10.1016/j.ijid.2021.12.343', 'article-title': 'Safety and tolerability of hydroxychloroquine in health care workers ' 'and first responders for the prevention of COVID-19', 'volume': '116', 'author': 'JE McKinnon', 'year': '2022', 'journal-title': 'WHIP COVID-19 Study. Int J Infect Dis'}, { 'key': 'pmed.1004428.ref018', 'doi-asserted-by': 'crossref', 'first-page': 'e0261980', 'DOI': '10.1371/journal.pone.0261980', 'article-title': 'Hydroxychloroquine for prophylaxis of COVID-19 in health workers: A ' 'randomized clinical trial.', 'volume': '17', 'author': 'J Rojas-Serrano', 'year': '2022', 'journal-title': 'PLoS ONE.'}, { 'key': 'pmed.1004428.ref019', 'doi-asserted-by': 'crossref', 'first-page': '40', 'DOI': '10.1016/j.ijid.2023.01.019', 'article-title': 'Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health ' 'care workers: a randomized, multicenter, placebo-controlled trial ' 'Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine ' '(HERO-HCQ).', 'volume': '129', 'author': 'S Naggie', 'year': '2023', 'journal-title': 'Int J Infect Dis'}, { 'issue': '1', 'key': 'pmed.1004428.ref020', 'doi-asserted-by': 'crossref', 'first-page': '85', 'DOI': '10.1016/j.cmi.2022.07.006', 'article-title': 'Daily tenofovir disoproxil fumarate/emtricitabine and ' 'hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a ' 'double-blind placebo-controlled randomized trial in healthcare workers', 'volume': '29', 'author': 'R Polo', 'year': '2022', 'journal-title': 'Clin Microbiol Infect'}, { 'issue': '6', 'key': 'pmed.1004428.ref021', 'doi-asserted-by': 'crossref', 'first-page': 'e059540', 'DOI': '10.1136/bmjopen-2021-059540', 'article-title': 'Hydroxychloroquine plus personal protective equipment versus personal ' 'protective equipment alone for the prevention of laboratory-confirmed ' 'COVID-19 infections among healthcare workers: a multicentre, ' 'parallel-group randomised controlled trial from India', 'volume': '12', 'author': 'BK Tirupakuzhi Vijayaraghavan', 'year': '2022', 'journal-title': 'BMJ Open'}, { 'issue': '1', 'key': 'pmed.1004428.ref022', 'doi-asserted-by': 'crossref', 'first-page': '22', 'DOI': '10.1186/s13104-023-06281-7', 'article-title': 'Hydroxychloroquine to prevent SARS-CoV-2 infection among healthcare ' 'workers: early termination of a phase 3, randomised, open-label, ' 'controlled clinical trial.', 'volume': '16', 'author': 'A Llanos-Cuentas', 'year': '2023', 'journal-title': 'BMC Res Notes'}, { 'key': 'pmed.1004428.ref023', 'first-page': '3', 'article-title': 'Efficacy of Hydroxychloroquine in Pre-exposure Severe Acute Respiratory ' 'Syndrome Coronavirus 2 Prophylaxis among High-Risk HealthCare Workers', 'volume': '12', 'author': 'E Nasri', 'year': '2023', 'journal-title': 'A Multicenter Study. Adv Biomed Res'}, { 'key': 'pmed.1004428.ref024', 'doi-asserted-by': 'crossref', 'first-page': '789', 'DOI': '10.1007/s10654-022-00891-4', 'article-title': 'Systematic review and meta-analysis of randomized trials of ' 'hydroxychloroquine for the prevention of COVID-19', 'volume': '37', 'author': 'X Garcia-Albeniz', 'year': '2022', 'journal-title': 'Eur J Epidemiol'}, { 'key': 'pmed.1004428.ref025', 'article-title': 'WHO Living guideline: Drugs to prevent COVID-19.', 'author': 'World Health Organization', 'year': '2023'}, { 'key': 'pmed.1004428.ref026', 'doi-asserted-by': 'crossref', 'first-page': '16', 'DOI': '10.1038/s41421-020-0156-0', 'article-title': 'Hydroxychloroquine, a less toxic derivative of chloroquine, is ' 'effective in inhibiting SARS-CoV-2 infection in vitro', 'volume': '6', 'author': 'J Liu', 'year': '2020', 'journal-title': 'Cell Discov'}, { 'key': 'pmed.1004428.ref027', 'doi-asserted-by': 'crossref', 'first-page': '732', 'DOI': '10.1093/cid/ciaa237', 'article-title': 'In Vitro Antiviral Activity and Projection of Optimized Dosing Design ' 'of Hydroxychloroquine for the Treatment of Severe Acute Respiratory ' 'Syndrome Coronavirus 2 (SARS-CoV-2).', 'volume': '71', 'author': 'X Yao', 'year': '2020', 'journal-title': 'Clin Infect Dis'}, { 'key': 'pmed.1004428.ref028', 'doi-asserted-by': 'crossref', 'first-page': '105121', 'DOI': '10.1016/j.jcv.2022.105121', 'article-title': 'A systematic review and meta-analysis of the accuracy of SARS-COV-2 IGM ' 'and IGG tests in individuals with COVID-19.', 'volume': '148', 'author': 'ACL Macedo', 'year': '2022', 'journal-title': 'J Clin Virol'}, { 'key': 'pmed.1004428.ref029', 'article-title': 'FDA cautions against use of hydroxychloroquine or chloroquine for ' 'COVID-19 outside of the hospital setting or a clinical trial due to ' 'risk of heart rhythm problems.', 'author': 'FDA US', 'year': '2023'}, { 'issue': '11', 'key': 'pmed.1004428.ref030', 'article-title': 'Feasibility of SARS-CoV-2 Antibody Testing in Remote Outpatient Trials.', 'volume': '8', 'author': 'SM Lofgren', 'year': '2021', 'journal-title': 'Open Forum Infect Dis.'}, { 'issue': '11', 'key': 'pmed.1004428.ref031', 'doi-asserted-by': 'crossref', 'DOI': '10.1093/ofid/ofaa500', 'article-title': 'Safety of Hydroxychloroquine Among Outpatient Clinical Trial ' 'Participants for COVID-19.', 'volume': '7', 'author': 'SM Lofgren', 'year': '2020', 'journal-title': 'Open Forum Infect Dis.'}, { 'key': 'pmed.1004428.ref032', 'doi-asserted-by': 'crossref', 'first-page': 'e71', 'DOI': '10.12688/wellcomeopenres.16741.1', 'article-title': 'The WHO guideline on drugs to prevent COVID-19: small numbers- big ' 'conclusions.', 'volume': '6', 'author': 'WH Schilling', 'year': '2021', 'journal-title': 'Wellcome Open Res'}, { 'key': 'pmed.1004428.ref033', 'doi-asserted-by': 'crossref', 'first-page': '741', 'DOI': '10.1016/S0140-6736(20)31821-3', 'article-title': 'World Health Organization Solidarity Vaccines Trial Expert Group. ' 'COVID-19 vaccine trials should seek worthwhile efficacy', 'volume': '396', 'author': 'P Krause', 'year': '2020', 'journal-title': 'Lancet'}], 'container-title': 'PLOS Medicine', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://dx.plos.org/10.1371/journal.pmed.1004428', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 9, 12]], 'date-time': '2024-09-12T17:40:39Z', 'timestamp': 1726162839000}, 'score': 1, 'resource': {'primary': {'URL': 'https://dx.plos.org/10.1371/journal.pmed.1004428'}}, 'subtitle': [], 'editor': [{'given': 'Jens-Ulrik', 'family': 'Jensen', 'sequence': 'first', 'affiliation': []}], 'short-title': [], 'issued': {'date-parts': [[2024, 9, 12]]}, 'references-count': 33, 'journal-issue': {'issue': '9', 'published-online': {'date-parts': [[2024, 9, 12]]}}, 'URL': 'http://dx.doi.org/10.1371/journal.pmed.1004428', 'relation': {}, 'ISSN': ['1549-1676'], 'subject': [], 'container-title-short': 'PLoS Med', 'published': {'date-parts': [[2024, 9, 12]]}}
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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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