Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1849 (Published 14 May 2020) Cite this as: BMJ 2020;369:m1849Read our latest coverage of the coronavirus pandemic
Linked Editorial
Lack of efficacy of hydroxychloroquine in covid-19
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Dear Editor
The multicentric study from China, despite having many limitations, clearly proves one thing beyond doubt: that Hydrochloroquine intake didn't improve time to recovery and survival.
However, they could also have assessed the improvement in symptoms which surely would have provided justification for HCQ intake.
Competing interests: No competing interests
Dear Editor
I read with great interest the paper published by Tang et al.[1]. The authors are trying to deliver the most wanted data that the scientific community is longing for. However, the article has many concerns and I hope to solve them after the author shares the data.
The first observation is about the inconsistencies between the Trial registration and the manuscript. Despite the incredible speed, the trial was registered on the same day when the Ethical committee approved it. Later modifications in the trial with the IRB were not reflected in the same speed.
Of note, in the ChicTr.org, inclusion criteria were patients with symptoms ≤12 days, from onset to randomisation. Oddly enough, the mean time , in days, from onset and randomisation was 16.6 (range from 3 to 41 days). The registered protocol does not mention interim analysis; yet, the authors stopped the trial in accordance with the independent data and safety monitoring committee, which was not mentioned in the ChicTr.org registration.
Fever was considered as a criterion for moderate disease; 84% of the sample had moderate disease, but the average temperature was 36.9ºC (±0.4). I believe that Table 1 may have some errors. Hemoglobin levels are written as 128.8 g/L, which may be an error.
Randomization is probably the most import aspect of a clinical trial, and details about blocks, by center, and if the envelopes were sealed and opaque were not mentioned, but the authors put this in the discussion.
A quite disturbing finding is related to a patient who was randomized to SOC and received hydroxychloroquine for 14 days, and 6, who were randomized to received hydroxychloroquine, were changed to the SOC group. Definitions of ITT and Per protocol were not identified. Without the data, we are not able to make the calculation.
In a Risk of Bias analysis [2], this article would receive low bias for random sequence generation, unclear about allocation concealment, high risk for blinding of participants and personnel, low risk for blinding of outcome assessment, low risk for incomplete outcome data, and high risk for selective outcome reporting for the difference between the manuscript and the published trial protocol.
In the heavily criticized [3] article published by Gautret et al., the French group used RT-PCR results as the main outcome in patients with a mean time between the onset of symptoms and inclusion 4 days [4]. Tang et al. used the same endpoint, RT-PCR in patients with mild disease, with an average, in days, from the onset of symptoms to initiation of the treatment 16.6 (+1 when they started to receive the drug.), plus 14 or 21 days of treatment, for moderate or severe disease, respectively. Thus, these two articles are not comparable.
We need to learn much more about this disease. The median duration of hospitalization has been reported as 12 days (mean 12.8), 91% of those who are admitted in hospital received a diagnosis of pneumonia from a physician [5]; the results presented in the Tang et al. study [1] do not replicate these data from a Chinese cohort. Actually, taking part in this study increased the time span of the disease, and reduced the development of pneumonia, since there is no reference to this condition in the study [1].
It seems very important that data sharing should be readily available with the publication of the study, as the French group did; with data, others may have their own analysis.
References
1 Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020;369:m1849.
2 Hopp L. Risk of bias reporting in Cochrane systematic reviews. International Journal of Nursing Practice. 2015;21:683–6. doi:10.1111/ijn.12252
3 eliesbik. Thoughts on the Gautret et al. paper about Hydroxychloroquine and Azithromycin treatment of COVID-19 infections. Science Integrity Digest. 2020.https://scienceintegritydigest.com/2020/03/24/thoughts-on-the-gautret-et... (accessed 17 May 2020).
4 Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;:105949.
5 Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020;382:1708–20.
Competing interests: No competing interests
Dear Editor,
Hydroxychloroquine(HCQ) has become the topic of discussion after the emergence of the COVID19 pandemic. The current use of the molecule mainly restricted to diseases like systemic lupus erythematosus(SLE), rheumatoid arthritis, and other various autoimmune rheumatic disorders(AIRD). History of anti-viral activity of chloroquine has been stated dates back in late 1960 when Inglot A. D. demonstrated in vitro anti-viral activity of chloroquine and nonsteroidal anti-inflammatory medications against encephalovirus, influenza A2, herpes simplex, vaccinia, Newcastle disease, and Sindbis. The anti-viral activity was mainly dependent on the serum concentration of the drug and pH of the media. [1] HCQ has similar pharmacokinetic properties like chloroquine, acts through increasing lysosomal pH of the antigen-presenting cell, and blocking TLR9 on plasmacytoid dendritic cell.[2] Despite having in vitro anti-viral activity, in the past, it has failed to show any clinical benefit in randomized control trial on influenza [3] and detrimental effect in the management of chikungunya. [4] After the emergence of COVID19 pandemic with initial few trials had shown modest benefit both in vitro[5] and small scale observational trials[6] the focus of care “shifts from the needs of the individual (ethical principle of autonomy) to the needs of the community as a whole(ethical principle of distributive justice)”[7] to serve the maximum number of people with highest possible benefit. Despite the fact that the trials have been criticized in the different forums [8,9,10], its use has been continued leading to the ‘potential shortage’ of HCQ for the SLE and other AIRD patients. [11]
The trial by Tang W et al. [12] on “Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019” is probably the history repeats itself. Although there are some concerns related to the article like delayed initiation of the treatment, no stratification based on severity or cytokine profiling to look for the baseline cytokine storm of the patients were the confounders and use of higher dose may be a probable explanation of the higher side effects, the randomization gives the edge over other recent relevant researches. It also echoes a similar observation of the recent observational trial and retrospective multicentric cohort analysis.[13,14] More similar multicentric randomized control trials are the need of the time to prevent further exposure to a drug with doubtful efficacy and to justify the “ethical principle of distributive justice.”
References:
1. Inglot, A.D., 1969. Comparison of the antiviral activity in vitro of some non-steroidal anti- inflammatory drugs. J. Gen. Virol. 4, 203–214. https://doi.org/10.1099/0022-1317- 4-2-203.
2. Schrezenmeier, E., Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.Nat Rev Rheumatol 16, 155–166 (2020). https://doi.org/10.1038/s41584-020-0372-x
3. Paton, N.I., Lee, L., Xu, Y., Ooi, E.E., Cheung, Y.B., Archuleta, S., Wong, G., Wilder-Smith, A., Smith, A.W., 2011. Chloroquine for influenza prevention: a randomised, double- blind, placebo controlled trial. Lancet Infect. Dis. 11, 677–683. https://doi.org/10. 1016/S1473-3099(11)70065-2.
4. Roques, P., Thiberville, S.-D., Dupuis-Maguiraga, L., Lum, F.-M., Labadie, K., Martinon, F., Gras, G., Lebon, P., Ng, L.F.P., de Lamballerie, X., Le Grand, R., 2018. Paradoxical effect of chloroquine treatment in enhancing chikungunya virus infection. Viruses 10. https://doi.org/10.3390/v10050268.
5. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. 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). Clin Infect Dis 2020;ciaa237. [doi: 10.1093/cid/ciaa237].
6. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID‐19: Results of an open‐label non‐randomized clinical trial. Int J Antimicrob Agents 2020;105949. [doi: 10.1016/j.ijantimicag. 2020.105949].
7. Hick JL, Rubinson L, O’Laughlin DT, Farmer JC. Clinical review: Allocating ventilators during large‐scale disasters–problems, planning, and process. Crit Care 2007;11:217.
8. Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ. 2020;369:m1432. Published 2020 Apr 8. doi:10.1136/bmj.m1432
9. Kim AH, Sparks JA, Liew JW, Putman MS, Berenbaum F, Duarte_García A, et al. For the COVID‐19 Global Rheumatology Alliance. A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID‐19. Ann Intern Med. 2020; [Epub ahead of print 30 March 2020]. doi: https://doi.org/10.7326/M20‐1223.
10. Chattopadhyay A, Mishra D, Sharma V, K Naidu GS, Sharma A. Coronavirus disease-19 and rheumatological disorders: A narrative review. Indian J Rheumatol 0;0:0.
11. B. Mehta, J. Salmon, S. Ibrahim, Potential Shortages of Hydroxychloroquine for Patients with Lupus During the Coronavirus Disease 2019 Pandemic, JAMA Health Forum 2020, 1, e200438.
12. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ [Internet]. 2020 May 14 [cited 2020 May 16];369. Available from: https://www.bmj.com/content/369/bmj.m1849
13. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxy- chloroquine in hospitalized patients with Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2012410.
14. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. Published online May 11, 2020. doi:10.1001/jama.2020.8630
Competing interests: No competing interests
Dear Editor
In addition to the work of Tang et al[1], several large observational trials of hydroxychloroquine, with or without azithromycin, in the treatment of COVID-19 pneumonia have recently been reported[2, 3]. A recent observational trial of famotidine in the treatment of COVID-19 pneumonia has also been reported in preliminary form[4]. It is important in the analysis of these studies that we do not miss key observations that may point us to possible mechanisms that could explain SARS-CoV-2 pathogenesis.
COVID-19 pathogenesis can be partially explained by infection of the dendritic cell and endothelial cells through ACE2/DC-SIGN/CD209 receptor complex on these cells as well as infection of the type II pneumocyte through its ACE2/L-SIGN/CD209 complex[5]. Hydroxychloroquine[6] and famotidine[7] are modulators of the dendritic cell. Such modulation could be expected to blunt the immune response and reduce levels of interleukin-6 (IL-6) C-reactive protein (CRP), and other inflammatory markers.
In a preprint of Tang et al[1] published online on Medxriv on 4/14/20[8], the authors reported that a significant efficacy of HCQ on alleviating symptoms was observed when the confounding effects of anti-viral agents were removed in a post-hoc analysis (Hazard ratio 8.83, 95%CI, 1.09 to 71.3). The authors also noted a significantly greater reduction of CRP (6.986 mg/L in SOC plus HCQ versus 2.72 mg/L in SOC alone, P=0.045) conferred by the addition of HCQ, which also led to more rapid recovery of lymphopenia (p=ns). These data are not present in the current report.
In a case control study, IL-6 levels were noted to decline in patients with COVID-19 pneumonia treated with hydroxychloroquine but not controls[9]. Levels of inflammatory markers in two observational studies of famotidine and hydroxychloroquine were not measured before and after completion of therapy[2, 4].
The observational studies of hydroxychloroquine[2, 3] did not control for famotidine use. In the observational trial of famotidine as treatment for COVID-19 pneumonia, while the difference did not appear to be statistically significant, famotidine was associated with a HR of intubation or death of 0.55 (95% CI 0.18-1.75), while the combination of famotidine and hydroxychloroquine was associated with a HR of intubation of death of 0.35 (95% CI 0.14-0.85)[4]. This should stimulate further exploration of levels of inflammatory markers in patients before and after initiation of therapy.
As the randomized clinical trials data on treatments for COVID-19 mature, models that involve modulation of dendritic cells infected by SARS-CoV-2 should be taken into account.
We declare no competing interests.
References
1. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. doi:10.1136/bmj.m1849
2. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine. 2020. doi:10.1056/NEJMoa2012410
3. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020. doi:10.1001/jama.2020.8630
4. Freedberg DE, Conigliaro J, Sobieszczyk ME, et al. Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Retrospective Cohort Study. medRxiv. 2020:2020.05.01.20086694. doi:10.1101/2020.05.01.20086694
5. Brufsky A, Lotze MT. DC/L-SIGNs of Hope in the COVID-19 Pandemic. Journal of Medical Virology. 2020; doi:10.1002/jmv.25980
6. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology. 2020;16(3):155-66. doi:10.1038/s41584-020-0372-x
7. Szeberényi JB, Pállinger É, Zsinkó M, et al. Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation. Immunology Letters. 2001;76(3):175-82. doi:10.1016/S0165-2478(01)00184-5
8. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv. 2020:2020.04.10.20060558. doi:10.1101/2020.04.10.20060558
9. Yu B, Wang DW, Li C. Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19. medRxiv. 2020:2020.04.27.20073379. doi:10.1101/2020.04.27.20073379
Competing interests: No competing interests
Dear Editor
I read with interest the article by Tang et al., where they report an open-label randomized trial of hydroxychloroquine (1200 mg on day 1-3 followed by 800 mg for 2-3 weeks depending upon disease severity) plus standard of care versus standard of care alone for adults with mild to moderate coronavirus disease 2019 (COVID-19) in sixteen hospitals across three provinces in China (1). The study, though open label, was a well-designed, multicentric, randomized controlled trial that was well conducted with no loss to follow-ups and study oversight by contract research organization.
However, Tang and colleagues' study was terminated early after one hundred fifty patients, less than half of the intended 360, were enrolled. The authors ascribed this not only to successful containment of COVID-19 in the areas but more importantly to difficulties faced in participant recruitment on account of multiple competing studies vying for identical participants. This left the trial underpowered and added to the list of missed opportunity studies attempting to determine efficacy and safety of hydroxychloroquine in COVID-19. Although HCQ has shown promise in earlier in vitro studies and few clinical observational studies (2–5), these signals must be rigorously confirmed or refuted in high-quality randomized trials—particularly since there are no proven safe and effective treatments for COVID-19 so far. The overall body of evidence for HCQ in COVID-19 has serious lacunae in terms of most studies having design flaws, suboptimal reporting, lack of control groups as well as being underpowered (6,7).
The scientific research community as well as worldwide public health systems are currently under immense pressures to contain the pandemic as well as to find an effective medical countermeasure. Given the early recognition of unprecedented scale of COVID-19 pandemic, the response from the global research community has been vigorous and encouraging. A review of trial registry- clinicaltrials.gov reveals more than 1500 registered COVID-19 studies with nearly 900 intervention trials being planned and conducted across the globe as of 15th May 2020 (8). However, it is imperative to understand that much of these studies are independent efforts concentrated in heavily burdened health systems that risk undermining their common, well-intentioned goals. Several clinical trials competing to enroll from the same pool of patients and utilizing common, and increasingly limited diagnostic and human resources especially in academic centers, could effectively impede each other’s progress and stymie efforts to develop safe and effective therapies. Even between centers, lack of co-ordination risks duplication of studies and consequent inefficiency. In the prevailing pandemic situation, with lives and livelihoods at stake and time being the essence, the need for well-coordinated and harmonized research efforts thus cannot be overemphasized. Although World Health Organization (WHO) and other global groups have formulated strategies that aim to collaborate and accelerate diagnostic, therapeutic as well as vaccine research (9–13), substantial organizational, administrative and political hurdles need to be overcome at the ground level to enable these centralized efforts. At the national level. regulatory agencies, health authorities and funding bodies need to take a lead by identifying most promising interventional strategies based on existing evidence and foster collaboration among established local investigators and trial sites to pursue high quality studies thus allowing adequate participant accrual and timely results. The institutional review boards can also play their part in such situations by adopting a policy whereby some studies are prioritized for recruitment over others based on predefined criteria with the goal of minimizing the studies that begin but fail to recruit enough participant and remain underpowered as in the case of Tang et al (14). Finally, the onus is on individual researchers and groups to identify and respond to calls for participation in larger well-designed studies with the goal to aid in timely recruitment and generation of results to support or refute the clinical hypothesis.
While the clinicians managing COVID-19 patients are understandably under enormous pressure to prescribe, embracing unproven interventions risks more harm than good and can potentially exacerbate the ongoing health and humanitarian crisis. Therefore, despite the new norm of social distancing, the need for global, national, and local research communities to combine efforts and coordinate their activities towards the shared goal of combating the pandemic through high quality robust clinical evidence, has never been greater.
References:
1. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ [Internet]. 2020 May 14 [cited 2020 May 16];369. Available from: https://www.bmj.com/content/369/bmj.m1849
2. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.
3. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. 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). Clin Infect Dis Off Publ Infect Dis Soc Am. 2020 Mar 9;
4. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents [Internet]. 2020 Mar 20 [cited 2020 May 2]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/
5. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre S, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-....
6. Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ [Internet]. 2020 Apr 8 [cited 2020 May 2];369. Available from: https://www.bmj.com/content/369/bmj.m1432
7. Alexander PE, Debono VB, Mammen MJ, Iorio A, Aryal K, Deng D, et al. COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine. J Clin Epidemiol. 2020 Apr 21;
8. Listed studies related to coronavirus disease (CoVID-19) [Internet]. Available from: https://clinicaltrials.gov/ct2/results?cond=COVID-19
9. R&D Blueprint and COVID-19 [Internet]. [cited 2020 May 16]. Available from: https://www.who.int/teams/blueprint/covid-19
10. Novel Coronavirus COVID-19 – GloPID-R [Internet]. [cited 2020 May 16]. Available from: https://www.glopid-r.org/our-work/novel-coronavirus-covid-19/
11. COVID-19 [Internet]. CEPI. [cited 2020 May 16]. Available from: https://cepi.net/covid-19/
12. COVID-19 Therapeutics Accelerator [Internet]. 1AD [cited 2020 May 16]. Available from: https://www.gatesfoundation.org/Media-Center/Press-Releases/2020/03/COVI...
13. Accelerating research on COVID-19 in resource-limited settings [Internet]. COVID-19 Clinical Research Coalition. [cited 2020 May 16]. Available from: https://covid19crc.org/
14. Gelinas L, Lynch HF, Bierer BE, Cohen IG. When clinical trials compete: prioritising study recruitment. J Med Ethics. 2017 Dec 1;43(12):803–9.
Competing interests: No competing interests
Dear Editor,
Treatment by HCQ posits that recovery is significantly faster (generally one week rather than a fortnight). This rises from field observations rather than clinical trials. Much has been made of that terrible fault - that treatment is prioritised over methodology.
The median is 20 days: https://www.cebm.net/covid-19/sars-cov-2-viral-load-and-the-severity-of-...
That is the median. in fact " Infectiousness was estimated to decline relatively quickly within 7 days of illness onset".
This study measures viral load after 28 days - by which time all survivors will have recovered anyway. It in no way tests whether patients taking it with azithromycine with HCQ recovered more quickly (7 days rather than 14), nor whether fewer died.
So as a proof the HCQ does not work as it's proponents claim, this study falls considerably short.
https://www.medrxiv.org/content/10.1101/2020.04.18.20063875v1 shows that where HCQ is used death rates are much lower. This needs examining honestly.
Basis for such a study should not be outlandishly difficult. What are the pre-lockdown figures of CV19 for Lupus sufferers, for example?
Competing interests: No competing interests
Dear Editor
Too little too late is right. The overwhelming evidence is that the severe manifestations of Covid-19 are due to cytokine storm and the mosr appropriate initial treatment is high dose steroid, with (I believe) an interleukin antagonist. Given the growing evidence, and indeed the development of protocols for early and aggressive therapy I am distressed that these are not being implemented immediately, and that my communications with senior figures in the NHS go ananswered. I first suggested this approach to the Chief Medical Officer over three weeks ago. If I am proved correct I believe that those who have subsequently lost relatives would have a good case to sue for negligence. As i have also argued, if treatment for the severe complications works tjen the risks and scare factor of coronavirus are substantially reduced.
So wjy does treatment not figure in the government's daily briefings? I have asked fruitlessly.
Competing interests: No competing interests
Dear Editor
Much global interest and accompanying public hope has surrounded the use of hydroxychloroquine (HCQ) in COVID-19 infection. HCQ acts on the upstream disease pathway in COVID-19 by blocking entry of SARS-CoV2 via ACE2 into respiratory epithelial cells, initially in the nose and then in the lung [1]. Hence the ideal scenario for testing efficacy of HCQ would be early on in the disease process before the onset of the cytokine cascade occurs.
The randomised controlled trial of Tang et al [2] suggests that use of high dose HCQ in 150 patients admitted to hospital with mainly persistent mild to moderate COVID-19 infection has no benefit compared to standard of care in terms of the primary outcome measure of viral elimination after 28 days. Furthermore, for the secondary end point there was no difference in alleviation of clinical symptoms, albeit relatively mild. Pointedly their patients had no evidence of cytokine mediated hyperinflammation in terms of a mean C reactive protein level of 8.6mg/l, along with normal values for mean oxygen saturation of 97% and lymphocyte count of 1500 cells/ul. Only 30% of patients had coexisting conditions and the mean age was 46 years, while there were no deaths reported during follow up.
The UK NIHR PRINCIPLE primary care trial will evaluate the use of HCQ as monotherapy compared to routine care in 3000 COVID-19 older susceptible patients including those in care homes, to assess if it might prevent progression to more severe disease involving hospital admission or death. It may not be possible to extrapolate the results of Tang et al to participants in PRINCIPLE where eligible patients may be those ≥ 50 years with comorbidity or ≥ 65 years without comorbidity. It will be particularly interesting to see if the presence of comorbidities in older more vulnerable patients with COVID-19 will result in HCQ being able to demonstrate disease modification effects in PRINCIPLE.
References
1. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16. doi: 10.1038/s41421-020-0156-0 [published Online First: 2020/03/21]
2. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020;369:m1849. doi: 10.1136/bmj.m1849
Competing interests: No competing interests
Dear Editor
This article sounds at first like a serious blow to the hydroxychloroquine hypothesis as it is a long awaited randomised trial.
Hydroxychloroquine has been documented In vitro since SARS1 and repeated in SARS2.(1)
Effect is significantly observed when given early in the disease (2-5 days) (2)
But as the article states the mean time before randomisation is 16,4 days.
So late treatment could explain the lack of effect for the mild to severe covid 19 patients.
Secondly, another mechanism of action for hydroxychloroquine is to control, hinder or alleviate the feared cytokine storm. But this is not an endpoint in this study so we do not know if the hydroxychloroquine group fared better in the long run.
Thirdly, the dose regiment is far above the recommended five days regimen 400 mg BID loading dose and 200 mg BID which could explain the unnormal representation of side effects.(3)
(1) Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–271. doi:10.1038/s41422-020-0282-0
(2) Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study. Preprints 2020, 2020050057 (doi: 10.20944/preprints202005.0057.v2).
(3) Clinical Infectious Diseases, ciaa237, https://doi.org/10.1093/cid/ciaa237
Competing interests: No competing interests
Re: Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial
Dear Editor:
HCQ has no killing effect on the virus unless a Zinc supplement is used. In addition, the Z-Pak was not given. HCQ requires the zinc supplement and the Z-Pak and Dr Raoult in France has used it in past Corona virus cases with excellent positive response. Therefore it isn't surprising that no effect was seen. This is a major flaw in the study design. HCQ opens a door into the cell for the zinc which shuts down viral RNA Replicase. https://www.medcram.com/ has a large series of segments on COVID-19 on its you tube channel.
Fresh Air and Sunlight were effective in the treatment of the Post-War Flu Pandemic a hundred years ago and for the treatment of TB prior to the discovery of INH.
The most effective treatment for COVID-19 is two doses of Ivermectin a week apart along with Doxycycline 200mg once then 100mg QD x 4 and again after the next dose of Ivermectin.
Competing interests: No competing interests