Effective post-exposure prophylaxis of Covid-19 is associated with use of hydroxychloroquine: Prospective re-analysis of a public dataset incorporating novel data
PhD, MRPharmS David M Wiseman, MD Pierre Kory, PhD, MB Samir A Saidi, PhD. d Dan Mazzucco
doi:10.1101/2020.11.29.20235218
BACKGROUND: A key trial (NCT04308668) of post-exposure prophylaxis found hydroxychloroquine-associated (HCQ) reductions of Covid-19 by 17% overall and 31% to 49% in subgroups. To understand these trends, we reanalyzed the dataset. METHODS: 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. RESULTS: Newly requested data missing from the dataset revealed that 52% and 19% of subjects received medication 1-2 days after intended and assumed overnight delivery or four-day intervention lag respectively. After re-analysis, we found reduced HCQ-associated incidence of Covid-19 with Early (up to 3 days post-exposure) (RR 0.58, 95%CI 0.35 -0.97; p=0.044; NNT 14.5) but not Late (RR 1.22, 95%CI 0.72 -2.04) prophylaxis. 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; p=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. Although, we did not detect effects of gender, folate, zinc, or ascorbate, confounding effects cannot be excluded. CONCLUSIONS: Using novel data and prospective re-analysis, hydroxychloroquine, in an age-dependent manner, was associated with reduced Covid-19 compatible illness when supplied for post-exposure prophylaxis between 1 and 3 days after high-or moderate-risk exposure, at higher loading and maintenance doses than in similar studies. The original study conclusions are controverted, and our finding warrants prospective confirmation.
Conflicts of Interest The sponsor is entirely responsible for its design and conduct. The sponsor and principal investigator have no financial or other conflicts of interest in the subject matter of this study. DMW is the president of Synechion, Inc. and KevMed, LLC, providing services for the medical industry and marketing medical products, respectively, outside of the area of this work. See ICMJE forms for further details. DM is the president of ZSX Medical, LLC. developing surgical devices and a Principal at Third Eye Associates, a technical consulting company. PK and SAS report no conflicts.
Data Sharing Microsoft Excel files will be available on reasonable request up to one year after publication to qualified investigators subject to an agreed upon data sharing agreement. The source dataset is available from the original authors.
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'indexed': {'date-parts': [[2022, 3, 29]], 'date-time': '2022-03-29T17:42:44Z', 'timestamp': 1648575764555},
'posted': {'date-parts': [[2020, 12, 2]]},
'group-title': 'Infectious Diseases (except HIV/AIDS)',
'reference-count': 40,
'publisher': 'Cold Spring Harbor Laboratory',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'accepted': {'date-parts': [[2020, 12, 11]]},
'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>',
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