Effective post-exposure prophylaxis of Covid-19 is associated with use of hydroxychloroquine: Prospective re-analysis of a public dataset incorporating novel data

DOI record: { "DOI": "10.1101/2020.11.29.20235218", "URL": "http://dx.doi.org/10.1101/2020.11.29.20235218", "abstract": "<jats:title>Abstract</jats:title><jats:sec><jats:title>BACKGROUND</jats:title><jats:p>A recent trial (<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04308668\">NCT04308668</jats:ext-link>) found that post-exposure prophylaxis with hydroxychloroquine (HCQ) was associated with a reduced incidence of Covid-19 by 17% overall; 36% in younger subjects, 31% in household contacts and 49% given within one day. To understand these trends, we re-analyzed the released dataset.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Our protocol conformed to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). We compared the incidence of Covid-19 after HCQ or placebo, stratifying by intervention lag, age, and gender.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Requesting additional data, we found that 52% of subjects received medication 1-2 days after the intended overnight delivery; 19% of them outside the intended four-day intervention lag. After re-analysis, there was a reduced incidence of Covid-19 associated with HCQ compared with placebo (9.6% vs. 16.5%) when received Early (up to 3 days) after exposure (RR 0.58, 95%CI 0.35 - 0.97; <jats:italic>p</jats:italic>=0.044; NNT 14.5) but not Late (RR 1.22, 95%CI 0.72 - 2.04).</jats:p><jats:p>We found a significant HCQ-associated Covid-19 reduction in subjects 18 to 45 years old with Early (RR 0.54, 95%CI 0.29-0.97; <jats:italic>p</jats:italic>=0.0448, NNT 11.5) but not Late (RR 1.02, 95%CI 0.55-1.89) prophylaxis, attenuated in older subjects (RR 0.75, 95%CI 0-27-2.05) and by co-morbidities. There were reductions associated with Early prophylaxis in household contacts (RR 0.35, 95%CI 0.13-0.89; p=0.025, NNT 5.7) and Health Care Workers (RR 0.74, 95%CI 0.4-1.38). We did not detect effects of gender, folate, zinc, or ascorbic acid.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Using novel data with a prospective <jats:italic>post hoc</jats:italic> re-analysis, hydroxychloroquine, in an age-dependent manner, was associated with reduced illness compatible with Covid-19 or confirmed infection when supplied for post-exposure prophylaxis between 1 and 3 days after high-risk or moderate-risk exposure, at higher loading and maintenance doses than in similar studies. This finding warrants prospective confirmation.</jats:p><jats:p>Registered with the Open Science Framework (last revised September 27, 2020, <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"http://osf.io/fqtnw\">osf.io/fqtnw</jats:ext-link>).</jats:p></jats:sec><jats:sec><jats:title>Short Summary</jats:title><jats:p>A prospective re-analysis of a public dataset integrated with novel data found an HCQ-associated reduction of illness compatible with Covid-19 when received between 1 and 3 days after a high-risk or moderate-risk exposure (RR 0.58, 95% CI 0.35-0.97, p=0.044, NNT14.5).</jats:p></jats:sec><jats:sec><jats:title>Plain Language Summary</jats:title><jats:p>A recent clinical trial examined the ability of hydroxychloroquine (HCQ) to prevent Covid-19 just after an exposure to a person confirmed to have Covid-19. There was an HCQ-associated reduction of Covid-19 by an overall 17%; 36% in younger subjects, and 49% in subjects given HCQ within one day of being exposed. Likely because the study had too few patients to find what may have been a medically and economically meaningful, reduction, this effect was not statistically significant.</jats:p><jats:p>Studying the trial data, we discovered an unintended and variable delay in the delivery of study drug which may have masked any drug effect. The investigators provided further information at our request that confirmed our theory. About half of the participants received drugs one or two days later than intended, about a fifth beyond the four days the investigators thought the drug might work.</jats:p><jats:p>When we factored in this new information, we found that if HCQ was given early (up to three days after exposure), it was associated with a statistically significant 42% reduction of Covid-19. Giving HCQ later had no effect. There was a greater effect in younger (less than 45 years) rather than older subjects (47% vs. 25%). Gender did not seem to affect the results, but there was a greater HCQ-associated reduction (65%) when it was given early to people exposed to Covid-19 in a household environment rather than to health care workers (26%). The effects associated with HCQ were better in people without co-existing conditions.</jats:p><jats:p>These re-calculations are important because the study, as originally analyzed, was the only randomized study that dealt with preventing Covid-19 cited by FDA to support a key public health decision made in June 2020 regarding HCQ. Although other studies have shown that the drug is not effective to treat established cases of Covid-19, our research suggests that that it is effective for prevention. Other prevention studies have failed to show a benefit of HCQ, possibly because they have used lower doses or have estimated the timing of dosing differently. Our research paves the way for our result to be confirmed under clinical trial conditions and for a re-examination of public health policy regarding this drug. Even with the introduction of vaccination, there remains a need for approaches like this to prevent Covid-19 while individual and community immunity develops, especially in subjects given a lower priority for vaccination.</jats:p></jats:sec>", "accepted": { "date-parts": [ [ 2020, 12, 11 ] ] }, "author": [ { "ORCID": "http://orcid.org/0000-0002-8367-6158", "affiliation": [], "authenticated-orcid": false, "family": "Wiseman", "given": "David M.", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-0816-9682", "affiliation": [], "authenticated-orcid": false, "family": "Kory", "given": "Pierre", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-5165-2461", "affiliation": [], "authenticated-orcid": false, "family": "Saidi", "given": "Samir A", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-3578-4610", "affiliation": [], "authenticated-orcid": false, "family": "Mazzucco", "given": "Dan", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2020, 12, 2 ] ], "date-time": "2020-12-02T20:34:58Z", "timestamp": 1606941298000 }, "deposited": { "date-parts": [ [ 2021, 1, 14 ] ], "date-time": "2021-01-14T08:37:19Z", "timestamp": 1610613439000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2022, 3, 29 ] ], "date-time": "2022-03-29T17:42:44Z", "timestamp": 1648575764555 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 2, "issued": { "date-parts": [ [ 2020, 12, 2 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2020.11.29.20235218", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2020, 12, 2 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2020, 12, 2 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2021011111255133000_2020.11.29.20235218v2.1", "unstructured": "World Health Organization. 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