Lack of protective effect of chloroquine derivatives on COVID-19 disease in a Spanish sample of chronically treated patients

Laplana et al., PLOS ONE, doi:10.1371/journal.pone.0243598, Sep 2020

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HCQ for COVID-19

1st treatment shown to reduce risk in March 2020, now with p < 0.00000000001 from 423 studies, used in 59 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

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Survey of 319 autoimmune disease patients taking CQ/HCQ with 5.3% COVID-19 incidence, compared to a control group from the general population (matched on age, sex, and region, but not adjusted for autoimmune disease), with 3.4% incidence.

It not clear why authors did not compare with autoimmune patients not on CQ/HCQ. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.0011, which is the observed real-world risk, taking into account factors such as these patients potentially being more careful to avoid exposure. If we adjust for the different baseline risk, the result becomes RR 0.36, p<0.001, suggesting a substantial benefit for HCQ/CQ treatment (as shown in other studies).

There may also be significant survey bias - those experiencing COVID-19 may be more likely to respond to the survey.

Authors note that they "could not eliminate completely the possibility of some bias due to the intrinsic condition of the individuals within the treatment group that are undergoing chloroquine or derivative drug treatment due to other diseases that alter their health status and may have different comorbidities", however they could account for one significant bias by comparing with matched autoimmune disease patients.

This study is excluded in the after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

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risk of case, 56.0% higher, RR 1.56, p = 0.24, treatment 17 of 319 (5.3%), control 11 of 319 (3.4%).

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1. Ferri et al., COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series, Clinical Rheumatology, doi:10.1007/s10067-020-05334-7.springer.com, doi.org.

Laplana et al., 9 Sep 2020, retrospective, Spain, peer-reviewed, survey, 3 authors.

This Paper HCQ All

Lack of protective effect of chloroquine derivatives on COVID-19 disease in a Spanish sample of chronically treated patients

Marina Laplana, Oriol Yuguero, Joan Fibla

PLOS ONE, doi:10.1371/journal.pone.0243598

Background The search for a SARS-CoV-2 treatment has emerged as a worldwide priority. We evaluated the role of chloroquine and its derivatives in COVID-19 in Spanish individuals. Methods We performed a survey addressed to patients regularly taking chloroquine and its derivatives for the control of their autoimmune diseases. The survey was distributed with special attention to Spanish patient associations centred on autoimmune diseases and rheumatology and to the general population. A sample of untreated subjects was matched to the treated group according to sex, age range and incidence region. COVID-19 disease prevalence was compared between treated and untreated-matched control sample. Results A total of 319 surveys of patients regularly taking chloroquine and its derivatives were recovered for further analysis. The prevalence of declared COVID-19 status in the treated group was 5.3% and the mean prevalence among the untreated-matched groups was 3.4%. A community exposition to COVID-19 was associated with a greater prevalence of COVID-19 in both, treated (17.0% vs. 3.2%; p-value<0.001) and untreated groups (13.4% vs. 1.1%; pvalue = 0.027). Conclusion We did not find differences of reported COVID-19 cases between treated and untreated groups, indicating a lack of protection by regular administration of chloroquine and its derivative drugs on COVID-19 infection. Of relevance, data indicates that patients that regularly take chloroquine derivatives are exposed to SARS-CoV-2 infection and must take the same protection measures as the general population.

References

Actualizacio ´n, Centro de Coordinacio ´n de Alertas y Emergencias Sanitarias. Direccio ´n general de salud pu ´blica, calidad e innovacio ´n

Boulware, Pullen, Bangdiwala, Pastick, Lofgren et al., A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19, N Engl J Med

Devaux, Rolain, Colson, Raoult, New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2020.105938

Emmi, Bettiol, Mattioli, Silvestri, Scala et al., SARS-CoV-2 infection among patients with systemic autoimmune diseases, Autoimmunity reviews, doi:10.1016/j.autrev.2020.102575

Gao, Tian, Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends, doi:10.5582/bst.2020.01047

Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2020.105949

Infante, Ricordi, Caprio, Fabbri, Hydroxychloroquine in the COVID-19 pandemic era: in pursuit of a rational use for prophylaxis of SARS-CoV-2 infection, Expert Rev Anti Infect Ther, doi:10.1080/14787210.2020.1799785

Joutei Hassani, Bennis, Hydroxychloroquine as antiviral prophylaxis for exposed caregivers to Covid-19: An urgent appraisal is needed, J Infect Public Health, doi:10.1016/j.jiph.2020.05.005

Keyaerts, Vijgen, Maes, Neyts, Van Ranst, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem Biophys Res Commun, doi:10.1016/j.bbrc.2004.08.085

Maa, Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases, Pharmacol Res Perspect, doi:10.1002/prp2.293

Principi, Esposito, Chloroquine or hydroxychloroquine for prophylaxis of COVID-19, Lancet Infect Dis, doi:10.1016/S1473-3099%2820%2930296-6

Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis, doi:10.1016/s1473-3099%2803%2900806-5

Thangaraju, Gurunthalingam, Venkatesan, Thangaraju, COVID-19: Wait for a novel drug or act with the age old drug-Do we have a choice?, J Infect Public Health, doi:10.1016/j.jiph.2020.05.006

Touret, De Lamballerie, Of chloroquine and COVID-19, Antiviral Res, doi:10.1016/j.antiviral.2020.104762

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The prevalence of declared COVID-19 status in the treated group was 5.3% and the mean prevalence among the untreated-matched groups was 3.4%. A community exposition to COVID-19 was associated with a greater prevalence of COVID-19 in both, treated (17.0% vs. 3.2%; p-value<0.001) and untreated groups (13.4% vs. 1.1%; p-value = 0.027).\n\n\nConclusion\nWe did not find differences of reported COVID-19 cases between treated and untreated groups, indicating a lack of protection by regular administration of chloroquine and its derivative drugs on COVID-19 infection. 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