Use of hydroxychloroquine in multidrug protocols for SARS-CoV-2

"Abstract

We review the available evidence supporting the use of hydroxychloroquine-based multidrug protocols in the treatment of COVID-19, in response to a recently published editorial in the Tasman Medical Journal...

Use of hydroxychloroquine for SARS-CoV-2

Clinicians understood quickly that no single drug was going to be necessary nor sufficient to treat acute COVID-19 with its three phases of viral replication, cytokine storm, and thrombosis. Hydroxychloroquine was part of the initial multidrug protocol used by Zelenko from March 2020...

Because Zelenko treated only high-risk patients, with increased likelihood of death relative to the general population, we can compare his case series against observed outcomes over the entire United States population. This comparison is biased towards the null hypothesis, however a positive result that overcomes this bias is sufficient.  For (N, a) = (405, 2) we obtained x0 = 1.8% and x1 = 4.0% and for (N, a) = (800, 2) we obtained x0 = 1.0% and x1 = 2.0%, using 95% confidence.15  During 2020, the case fatality rate (CFR) in the United States ranged between 2% and 6%.  Using p1 = 2%, it follows that by the end of April 2020 the mortality rate reduction benefit was supported by the preponderance of evidence, with crossover to clear and convincing by June 2020.  Similar analysis shows clear and convincing hospitalization rate reduction by the end of April 2020.

Furthermore, from a case series of 10,429 outpatients, treated in Marseilles, France by Raoult’s group in the IHU Mediterranee Infection Institute with hydroxychloroquine and azithromycin, in addition to standard of care, through the end of December 2020, we identified a case series of 1495 high-risk patients (age ≥ 60 years) with 5 reported deaths, whereas no deaths were reported for the other 8,934 patients.  Using (N, a) = (1495, 5) gives a random selection bias threshold x1 = 1.4% for 95% confidence which compares favourably with the CFR [case fatality rate] in France which ranged from 2% to above 14% during 2020, indicating a clear and convincing finding of mortality rate reduction.

Conclusion

It is our interpretation that hydroxychloroquine played an important role in preventing hospitalizations and deaths due to COVID-19, particularly in 2020 with the  more virulent strains. Widespread use of nasal sprays and gargles, aspirin, vitamin D, ivermectin, nirmatrelvir/ritonavir, molnupiravir, favipiravir, colchicine, corticosteroids, and anticoagulants (Fig. 1) in protocols all contributed to the benefits of early treatment which were widely favored over therapeutic nihilism in the pre-hospital phase. In case of a future pandemic, involving a novel disease, doctors should be encouraged to attempt treatments with repurposed medications based on biological plausibility, signals of benefit, and acceptable safety. Article 37 of the 2013 Helsinki declaration allows the use of unproven treatments if 'proven interventions do not exist or other known interventions have been ineffective' and the unproven treatment 'offers hope of saving life, reestablishing health or alleviating suffering'."