Does Clinical Trial on Hydroxychloroquine Support the Clinical Practice for COVID-19?

Amid COVID-19 global pandemic, multiple treatment options are tested and recommended by scientific and regulatory authorities followed  by evidence synthesis. Drugs in this list are Dexamethasone, Ramdesivir, Hydroxychlroquine, Chloroquine etc. Among all these globally recommended treatment options, Hydroxychloroquine shows the most contradictory and controversial result. Multiple Clinical Trials are being registered and conducted in various countries including China and US. Recently published comprehensive study on Hydroxychloroquine comparing it's efficacy with standard care completely shattered it's use in management of Coronavius infection. Here, I will be discussing about the evidence based upon the findings of trial conducted in Brazil.

What is Hydroxychloroquine ?

1. HCQ is the hydroxylated form of chloroquine; currently in use to treat various autoimmune diseases like Rheumatoid arthritis (RA), systemic lupus erythematosus(SLE) with much less side effects than Chloroquine. 
2. Structurally similar to it's parent compound Chloroquine, widespread prophylactic medication for Malarial infection. overdose of which causes acute poisoning leading to death. 
3. Because of it's chemical nature, hydroxychloroquine is weak base with immunomodulator property, HCQ was considered as a potent candidate to treat novel corona virus since outspread. 

Promising Pre-Clinical finding

As per the editorial  published in "The Nature" on 18 Mar 2020, Hydroxychloroquine was found to be effective to control SARS-COV-2 infection as per the in-vitro study. During the experimentations, Antiviral effect of HCQ was compared with Chloroquine (HC) for SARS-COV-2 infection  by in-vitro method. Dose response curve was plotted against SARS-COV-2 at four different multiplicities of infections (MOI). Viral RNA copy number was quantified and plotted post infection. 50 % Maximum effective concentration for Hydroxychloroquine was found to be significantly higher than chloroquine against all 4 MOIs. The observed result for effective concentration (EC50) was found to be statistically significant. In same study, significant changes in morphology of Early Endosomes (EEs) and Endolysosomes (ELs) was noticed, which ultimately impacted the transport of virus inside cells and tissues. 

Based upon the evidences like this, few government authorities, Including that of Brazil have approved the use of Chloroquine and Hydroxychlorquine for the management of severe Coronavirus infection. Subsequently, prescription of HCQ has increased post COVID all over the world with record braking mark of   2000% in United State. This overwhelming use was based upon few  clinical and non-clinical data with scant evidence. 

       What Does Recent Clinical Trial Finding Suggest ?

As per the recent publication on New England Journal of Medicine on 23 Jul 2020, there was no clinical improvements in the hospitalized patients with COVID-19 by administration of Hydroxychloroquine with or without Azithromycin on 15 Days as compared to standard care.

Multi-center, randomized, open label, controlled study was conducted in 55 different hospitals in Brazil on 667 patients - 504 confirmed COVID-19 cases where Hydroxychloroquine  was administered either standalone or in combination with Azithromycin for the period of 15 days post hospitalization. One group of patients were administered standard care as control, another two experimental groups with Hydroxychloroquine ((400 mg twice daily) alone and combined with Azithromycin respectively in 1:1:1 ratio. Here, standard care means administration of drugs from glucocorticoids, other immunomodulators, antibiotics and antiviral therapy group, where treating doctor can make their own choice. Clinical status was considered as primary outcome and recorded on following nominal scale. 

1. Not hospitalized with no limitation in activities
2. Not hospitalized with limitation in activities
3. Hospitalized but no oxygen supplementation
4. Hospitalized and providing supplemental oxygen
5. Hospitalized and oxygen supplemented through high flow nasal canula / non-invasive ventilation
6. Hospitalized with mechanical ventilation 
7. Death 

Statistical analysis of this data was performed by Mixed ordinal logistic regression method. Odd's ratio calculation for HCQ + Azithromycin versus control was 0.99, HCQ alone versus control, 1.21 and HCQ + Azithromycin versus HCQ alone was 0.82 with confidence interval of 95%. 

Conclusion

Based upon the finding of above mentioned study, Hydroxychloroquine is not an treatment option for COVID-19 infected patients. Considering few earlier randomized double blind study conducted in United state, Hydroxychloroquine is also not an prophylaxis for COVID-19 infection. 

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 6, 16 (2020). https://doi.org/10.1038/s41421-020-0156-0
2. https://www.saude.gov.br/noticias/agencia-saude/46601-cloroquina-podera-ser-usada-em-casos-graves-do-coronavirus
3. https://www.nejm.org/doi/full/10.1056/NEJMoa2019014