A living WHO guideline on drugs to prevent covid-19
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n526 (Published 02 March 2021) Cite this as: BMJ 2021;372:n526©BMJ Publishing Group Limited.
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Prophylaxis against covid-19
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Dear Editor,
The WHO guideline on “Drugs to prevent COVID-19” describes “high certainty” evidence from randomised controlled trials (RCTs) that hydroxychloroquine prophylaxis neither reduces mortality nor reduces hospital admission, and “moderate certainty” evidence of poor tolerability indicated by a significantly increased rate of adverse events (AEs) leading to drug discontinuation (1,2). Yet in the three pre-exposure prophylaxis RCTs evaluated in the guideline there were no deaths and only two COVID-19-related hospital admissions, and there was a mistake in the analysis of the number of discontinuations (after correction there is no longer a statistically significant difference between those taking the drug and the controls). Despite this the WHO guideline group has taken the unusual step of advising funders and researchers that they should “reconsider” ongoing trials, i.e. they should stop.
There is certainly not enough evidence to recommend hydroxychloroquine for COVID-19 prophylaxis (there never has been), and there is no doubt that it is ineffective in hospitalised patients (3), but is the small and heterogeneous evidence base that contributed to the formulation of the WHO guideline really enough to state conclusively, as the panel has done, that hydroxychloroquine does not provide a modest but worthwhile benefit (4)?
Antivirals, if they are effective, would be expected to provide greatest benefit early in the course of an individual COVID-19 infection, when viral burdens are greatest, and not in severely ill hospitalised patients when inflammatory processes dominate. Results in hospitalised patients should not be pooled with results from ambulant people who are well or mildly ill (5). The evidence base for hydroxychloroquine prophylaxis in COVID-19 assessed by the WHO guideline group comprises three RCTs in post-exposure prophylaxis (PEP- which approximates to early COVID-19 treatment) and only three in pre-exposure prophylaxis (PrEP- true COVID-19 prevention) (1, 2). Two studies used confirmed or suspected COVID-19 (mainly suspected) as their primary endpoints, and the other four used laboratory-confirmed COVID-19. Dosages differed. The largest PrEP study (>75% of the PrEP data) used a low hydroxychloroquine dose, similar to that used in antimalarial chemoprophylaxis, rather than the rheumatoid arthritis doses used in most other COVID-19 prophylaxis trials (7). All the data from the six RCTs were collected either in North America or Europe. These six RCTs enrolled 6,059 participants, but provided few endpoints (suspected or confirmed COVID-19, hospital admission or death). One PrEP study reported only one case of COVID-19 (6). In the three PrEP trials there were only 26 confirmed COVID-19 cases in total (15 out of 1,197 [1.25%] randomised to hydroxychloroquine, 11 out of 687 [1.6%] randomised to placebo).
With considerable heterogeneity between RCTs and so few events, the meta-analysis is sensitive to the methods employed. A previous meta-analysis evaluated the appropriately adjusted primary endpoints reported in each hydroxychloroquine prevention study (e.g. one study was a cluster randomised trial (8) so adjustment for cluster was necessary) (9). This review estimated a meta-analytic risk ratio of 0.86 (95% confidence interval [CI] 0.70 to 1.06). By contrast, the WHO guideline (1, 2) used laboratory confirmed COVID-19 (asymptomatic and symptomatic) for the primary endpoint in their meta-analysis of virological effect, without intra-study adjustments, and reports a meta-analytic odds ratio of 1.03 (95% CI 0.80 to 1.32) (10). This sensitivity with respect to the methodology indicates equipoise rather than definitive proof of lack of efficacy.
The WHO guideline development panel made the decision that “Mortality would be the outcome most important to individuals, followed by need for hospital admission, laboratory confirmed SARS-CoV-2 infection, and adverse effects leading to discontinuation” (1, 2). The review determined that there were no important differences in mortality, admission to hospital, or laboratory confirmed COVID-19 in the six RCTs, and that the evidence quality to support these statements was high. The 4-star “High GRADE rating” is defined as: “the authors have a lot of confidence that the true effect is similar to the estimated effect” (11). In the six prophylaxis RCTs evaluated there were no deaths at all in five trials and 13 deaths in the sixth, a non-blinded cluster-randomised PEP trial (8). Five deaths were in subjects allocated hydroxychloroquine (although one took no drug) and eight were in subjects allocated to no drug. In summary, without a single death in the three PrEP RCTs, and a highly unstable odds ratio of 0.67 for mortality in subjects allocated to hydroxychloroquine versus those who were not in the PEP RCTs (95% CI 0.22 to 2.05), the panel were able to conclude definitively that this provided “high certainty evidence” that hydroxychloroquine pre-exposure prophylaxis does not reduce COVID-19 mortality (1, 2). For the “second most important outcome” there were only 49 hospital admissions in total (20 in the PrEP RCTs; 11 hydroxychloroquine, 9 placebo) in the six RCTs. In the PrEP studies only two admissions were for COVID-19. These limited data clearly do not exclude modest but clinically significant differences. It is difficult to understand how this could ever be described as “high certainty evidence”.
These evaluations should be compared and contrasted with the earlier assessment by the WHO guideline group of dexamethasone and hydroxychloroquine in hospitalised COVID-19 patients (12, 13). Their judgement in September 2020 (12) was based on the very large platform RCT (RECOVERY), in which there were 980 deaths (14). The odds ratio for death in dexamethasone recipients receiving respiratory support was 0.82 (95% CI 0.72 to 0.92). For hydroxychloroquine, lack of efficacy was concluded from the outcomes of 10,859 mainly hospitalised patients (almost half from the RECOVERY trial) with over 2,000 deaths. The stratified meta-analytic estimate for mortality when combining data from the RECOVERY (14) and SOLIDARITY (15) trials (these data amount to 60% of all hospitalised patients and both trials used the same hydroxychloroquine dosage) resulted in a 95% CI for the risk ratio of 0.98 to 1.21 (15). Yet both of these transformative results were graded as “moderate certainty evidence” (defined as: “the true effect is probably close to the estimated effect”) with serious risk of bias (13). So somehow these effect estimates (and thus the certainty of the treatment recommendations) in severe COVID-19, based on thousands of deaths in well conducted RCTs, are considered less certain (i.e. less reliable) than an estimate for hydroxychloroquine prophylaxis derived from 13 deaths (1).
In justifying the “strong” negative recommendation, the WHO guideline states that hydroxychloroquine “probably increases the risk of adverse effects leading to discontinuation of the drug (moderate certainty)” (1, 2). It is arguable whether it is correct to pool toxicity assessments across different dose regimens, whether the more subjective measure of “discontinuation” should be evaluated rather than standardised severity gradings for AEs, and whether non-placebo-controlled evidence should be included. But aside from these reservations there is an important mistake in the calculations. The WHO meta-analysis miscoded the number of AEs in the study by Grau-Pujol et al. (6). There were more discontinuations in the placebo group (n=5) than in the hydroxychloroquine group (n=1), and not the other way round. After correction for the miscoded discontinuations due to AEs, there is no longer a significant difference between hydroxychloroquine and placebo recipients in premature study discontinuations (we used an inverse variance method to pool estimates as implemented in the R package meta; the fixed-effects model estimates a 95% CI for the odds ratio of 0.83-3.29). This emphasises the danger of issuing “strong” recommendations on the basis of limited and unstable data.
By making “strong” recommendations on the basis of scanty evidence (some of which is incorrect), and suggesting that trials should stop, the WHO committee has decided that if efficacy were to be shown by continuing current trials (a 30% reduction in the risk of symptomatic COVID-19 is compatible with the results from these trials (1, 2)), then hydroxychloroquine should still not be used. WHO recommendations are very influential and must be taken very seriously, and these may well stop all ongoing hydroxychloroquine studies. Once closed, clinical trials will not reopen. More data will come from recently completed trials (16) but, if these are not decisive, we may never know the truth.
It is reasonable to conclude already that hydroxychloroquine does not provide high efficacy in prevention or early treatment. At best it might have modest protective efficacy. Nevertheless, it is still widely recommended and used. If it really does not work this should stop. On the other hand, an inexpensive, well established, widely available and relatively well tolerated drug providing moderate preventive efficacy would still be valuable- particularly in countries waiting for vaccines and as a contingency if outbreaks of vaccine escape mutations occur. Solid and convincing evidence of benefit, or lack of benefit, is needed urgently. The guideline group recommended that “resources should rather be oriented to evaluate other more promising drugs to prevent COVID-19”. Recently registered trials are not proposing to evaluate hydroxychloroquine, so the main purpose of this recommendation seems to be to stop ongoing trials. We appreciate the urgency of COVID-19 and the need to accelerate research and share research outputs so that responsible guidance can be provided rapidly. Guidelines on the prevention and treatment of COVID-19 should be based on sufficient verified evidence, understanding of the disease process, sound statistical analysis and interpretation, and an appreciation of global needs.
William HK Schilling [1,2], James J Callery [1,2], Arjun Chandna [1,3], Raph L Hamers [1,4], James A Watson [1,2], Nicholas J White [1,2]
1. Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, UK
2. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
3. Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia
4. Eijkman Oxford Clinical Research Unit, Jakarta, Indonesia
REFERENCES
1. World Health Organization. Drugs to prevent COVID-19: A WHO living guideline. https://www.who.int/publications/i/item/WHO-2019-nCoV-prophylaxes-2021-1. accessed 11 March 2021.
2. Lamontagne F, Agoritsas T, Siemieniuk R, Rochwerg B, Bartoszko J, Askie L, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021;372:n526.
3. RECOVERY collaboratie group, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 383: 2030-20403.
4. Schilling WHK, Callery JJ, Chandna A, Hamers RL, Watson JA, White NJ. The WHO guideline on drugs to prevent COVID-19: small numbers- big conclusions. Wellcome Open, in press.
5. White NJ, Strub-Wourgaft N, Faiz A, Guerin PJ. Guidelines should not pool evidence from uncomplicated and severe COVID-19. Lancet, Mar 22: S0140-6736(21)00469-4. doi: 10.1016/S0140-6736(21)00469-4.
6. Grau-Pujol B , Camprubí D, Marti-Soler H, Fernández-Pardos M, Carreras-Abad C, Velasco de Andrés M et al. Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: initial results of a double-blind, placebo-controlled randomized clinical trial. PREPRINT (Version 1) available at Research Square [+https://doiorg/1021203/rs3rs-72132/v1+]. 2020.
7. Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, et al. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial. Clin Infect Dis. 2020: doi: 10.1093/cid/ciaa1571.
8. Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebé C, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med. 2021; 384: 417-427.
9. García-Albéniz X, Amo Jd, Polo R, Morales-Asencio JM, Hernán MA. Systematic review and meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19. medRxiv. 2021:2020.09.29.20203869.
10. Bartoszko JJ, Siemieniuk RA, Kum E, Qasim A, Zeraatkar D, Ge L, et al. Prophylaxis for covid-19: living systematic review and network meta-analysis. medRxiv. 2021:2021.02.24.21250469.
11. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336: 924-6.
12. World Health Organization. Corticosteroids for COVID-19. https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-20....
Accessed 11 March 2021.
13. World Health Organization. Therapeutics and COVID-19.
https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2020.1. Accessed 11 March 2021.
14. RECOVERY collaborative group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384: 693-704.
15. SOLIDARITY, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021; 384: 497-511.
16. Hernandez A, Patient-Centered Outcomes Research Unit, Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ). In: ClinicalTrials.gov [cited 2021 Mar 13]. Available from https://clinicaltrials.gov/ct2/show/NCT04334148.
Competing interests: The authors are all investigators on the COPCOV study; Chloroquine/hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting; a randomised, placebo-controlled prophylaxis study.
Dear Editor
Because uncertainty about which drugs, if any, are effective, COVID-19 prevention by vaccines has a major role to fight the disease.
In the face of low safe and effective vaccine availability, we suppose that reduced-dose of intradermal COVID-19 vaccine could preserve immunogenicity and safety.
This hypothesis is suggested by the recent published systematic review and meta-analysis that found that immunogenicity resulting from 3-µg, 6-µg, 7.5-µg and 9-µg influenza intradermal vaccination doses was not significantly different from full-dose 15-µg intramuscular vaccination for most viral strains, irrespective of patient age (1).
The results for immunogenicity and safety outcomes for this systematic review and meta-analysis were derived from only randomized clinical trials. This suggests a high level of evidence for these outcomes. The cohort study data were only included in the meta-analysis for influenza or influenza-like illness (1).
If this hypothesis will be confirmed by studies, there could be an important increase of COVID-19 vaccine availability all over the world.
Egunsola O, Clement F, Taplin J, et al. Immunogenicity and Safety of Reduced-Dose Intradermal vs Intramuscular Influenza Vaccines: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021;4(2):e2035693. doi:10.1001/jamanetworkopen.2020.35693
Competing interests: No competing interests
Dear Editor,
The Guideline clearly states that people who do Not Have Covid 19 should not take Hydroxychloroquine to Prevent Catching Covid 19. However, no mention is made of the studies that show the drug can help persons who have already caught Covid 19. My understanding is that Hydroxychloroquine can reduce symptoms. Unfortuneately, the press seems to take the results from the study as meaning there is no benefit from Hydroxychloroquine at any point in the disease progression. This is a case where WHO's excellent study about preventing Covid 19 is being used to detract from a drug that I understand can assist with various phases of some patient's Covid disease.
Am I missing something?
Thank you,
Jim Dokoozian
Competing interests: No competing interests
Dear Editor
The WHO Guideline seems to be the latest attempt to discredit hydroxychloroquine (HCQ) pre-exposure prophylaxis (PrEP) for COVID-19.
The article cites 7 studies that allegedly show that HCQ PrEP doesn't work (see below). The first study (Ref #3) is a meta-analysis of the same inappropriate studies described here. Refs #5 and #6 are POSTEXPOSURE studies (even says so in the title), and so is ref #8 ("Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient"). That leaves refs #4, #7 and #9. All three studies were seriously underpowered to draw conclusions about HCQ efficacy because HCQ had become so politically controversial that nobody would sign up for the studies (eg from ref #7, "Consequently, our study design deemed underpowered to evaluate any benefit regarding PrEP efficacy").
Conflating HCQ PrEP with postexposure prophylaxis and/or treatment of infected patients has led to misguided analysis and premature dismissal of this valuable approach to prevention of COVID-19, an approach that could save thousands of lives while we wait for nascent vaccines to reach the public. See the investigation of HCQ PrEP in the Indian healthcare worker cohort studies below and related articles.
3. Bartoszko JJ, Siemieniuk R, Kum E, etal. Prophylaxis against covid-19: living systematic review
and network meta-analysis (in peer-review). MedRxiv 2021https://www.medrxiv.org/content/10.1101/2021.02.24.21250469v1.
4. Abella BS, Jolkovsky EL, Biney BT, etal. Prevention and Treatment of COVID-19 With
Hydroxychloroquine (PATCH) Investigators. Efficacy and safety of hydroxychloroquine vs placebo
for pre-exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical
trial. JAMA Intern Med 2021;181:195-202. doi: 10.1001/jamainternmed.2020.6319 pmid: 33001138
5. Barnabas RV, Brown ER, Bershteyn A, etal. Hydroxychloroquine as postexposure prophylaxis
to prevent severe acute respiratory syndrome coronavirus 2 infection: a randomized trial. Ann
Intern Med 2020; doi: 10.7326/M20-6519. pmid: 33284679
6. Boulware DR, Pullen MF, Bangdiwala AS, etal. A randomized trial of hydroxychloroquine as
postexposure prophylaxis for Covid-19. N Engl J Med 2020;383:517-25.
doi: 10.1056/NEJMoa2016638 pmid: 32492293
7. Grau-Pujol B, Camprubí D, Marti-Soler H, etal. Pre-exposure prophylaxis with hydroxychloroquine
for COVID-19: initial results of a double-blind, placebo-controlled randomized clinical trial. Research
Square 2021; doi: 10.21203/rs.3.rs-72132/v1.
8. Mitjà O, Corbacho-Monné M, Ubals M, etalBCN-PEP-CoV2 Research Group. A cluster-randomized
trial of hydroxychloroquine for prevention of Covid-19. N Engl J Med 2021;384:417-27.
doi: 10.1056/NEJMoa2021801 pmid: 33289973
9. Rajasingham R, Bangdiwala AS, Nicol MR, etal. Hydroxychloroquine as pre-exposure prophylaxis
for COVID-19 in healthcare workers: a randomized trial. Clin Infect Dis 2020;ciaa1571.
doi: 10.1093/cid/ciaa1571. pmid: 33068425
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HCQ PrEP Studies in Healthcare Workers from India
1. Chatterjee P, Anand T, Singh KJ, et al. Healthcare workers and SARS-CoV-2 infection in India: a case-control investigation in the time of COVID-19. Indian J Med Res. 2020;151(5):459–467. doi:10.4103/ijmr.IJMR_2234_2039.
2. Bhattacharya R, Chowdhury S, Mukherjee R, et al. Pre exposure hydroxychloroquine use is associated with reduced COVID19 risk in healthcare workers. MedRxiv. 2020. doi:10.1101/2020.06. 09.2011680640.
3. Khurana A, Kaushal GP, Gupta R, Verma V, Sharma K, Kohli M. Prevalence and clinical correlates of COVID-19 outbreak among health care workers in a tertiary level hospital in Delhi. MedRxiv. 2020. doi:10.1101/2020.07.21.2015930141.
4. Goenka MK, Afzalpurkar S, Goenka U, et al. Seroprevalence of COVID-19 amongst health care workers in a tertiary care hospital of a metropolitan city from India. Lancet Reg Health. 2020;3:100041. doi:10.1016/j.lanwpc.2020.10004142.
5. Yadav RM, Pate A, Shankarkumar A, et al. Sero-survey for health-care workers provides corroborative evidence for the effectiveness of Hydroxychloroquine prophylaxis against COVID-19 infection. September 2020. https://www.researchgate.net/publication/344221734
Total number of subjects: 2,660
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Stricker RB, Fesler MC. A novel plan to deal with SARS‐CoV‐2 and COVID‐19 disease. J Med Virol. 2020; 92:1394–1395.
https://pubmed.ncbi.nlm.nih.gov/32343423/
Stricker RB, Fesler MC. Flattening the risk: Pre-exposure prophylaxis for COVID‐19. Infect Drug Resist 2020;13:3689–3694.
https://test.dovepress.com/articles.php?article_id=58280
Fesler MC, Stricker RB. Pre-exposure prophylaxis for COVID-19 in pregnant women. Int J Gen Med. 2021;14:279-284.
https://www.dovepress.com/articles.php?article_id=61495
Competing interests: No competing interests
Dear Editor
Who is the target audience for this? Isn't it about time this type of information is created for the benefit of a lay audience, especially those who have been most impacted by the SARS-2-CoV pandemic?
This raises issues of health literacy and understandability but these are not unsurmountable barriers - the infographic should be the first priority. #justsaying
Competing interests: No competing interests
Dear Editor,
The living systematic review and network meta-analysis are very helpful for daily practice in combating COVID-19. The authors find a promising non statistically significant effect of hydroxychloroquine prophylaxis on mortality with an OR 0.70, (95% CI 0.24 to 1.99) compared to placebo. As a comparison, the OR on mortality of dexamethasone treatment in patients receiving oxygen without invasive mechanical ventilation admitted for COVID-19 is 0.82 (95% CI, 0.72 to 0.94) (N Engl J Med 2021; 384:693-704) and is recommended and commonplace in daily practice.
With such a possible huge impact on mortality shouldn't the authors recommend further trials for (post-exposure) prophylactic use of hydroxychloroquine in patients with a high-risk profile, such as elderly with obesity?
Competing interests: No competing interests
Re: A living WHO guideline on drugs to prevent covid-19
Dear Editor,
It is regrettable that this article will serve only to confuse both medical and lay readers.
I have made the point many times that confusion arises from the improper interchangeability of the terms "SARS-CoV-2" and "Covid-19". They are not the same. Covid-19 is a specific syndrome of severe illness due to the induction of a hyperimmune state (cytokine storm, CSS) by infection with SARS-CoV-2. Thus preventing Covid-19 requires prevention of the development of that hyperimmune state. As the risk of such development depends on several factors (including genetic susceptibility) it is far from certain that SARS-CoV-2 infection will progress to Covid-19 and anyway the risk from more recent virus variants has clearly diminished substantially. But as one cannot predict in advance, the whole concept of preventing Covid-19 is an oxymoron and discussion of prophylaxis is a waste of time.
The vast majority of cases of SARS-CoV-2 infection develop little more than a bad cold or flu-like illness. So is the application of any antiviral drug actually necessary? I think not. What is necessary is a system for promptly identifying incipient Covid-19 (by measuring oxygen saturation in the first instance, and applying appropriate blood tests such as CRP, fibrinogen, D-dimer, platelet count etc) and then appropriately treating that developing cytokine storm with steroids and biologics. One could argue that hydroxychloroquine, a weak immune modulator, might have a role alongside these but none of the trials have employed it specifically in that capacity, and in any case if one was to extrapolate from its use in inflammatory joint disease one would use it in combination or not at all, as there are things that work better. So discussing the hydroxychloroquine evidence is also a waste of time.
SARS-CoV-2 infection is not the only thing that can precipitate a cytokine storm and I remain baffled by the apparent failure of almost every commentator to realise this. We need a hard reset based on longstanding management of the syndrome - which in my view requires everyone to read Cron and Behrens textbook (1). The reaction to the appearance of SARS-CoV-2 was, in retrospect, one of panic and hysteria. Most people need no treatment. Those that do should have the correct treatment applied promptly.
(1) Cron R, Behrens E. Cytokine Storm Syndrome. Springer, 2019
Competing interests: No competing interests