The usefulness of hydroxychloroquine (HCQ) in Covid-19 has been controversial, without clarity or clear evidence one way or the other, until very recently. A study on more than 2,500 patients in six units under the Henry Ford Hospitals group in Detroit, Michigan, USA, peer-reviewed, accepted and ready for publication in the International Journal of Infectious Diseases, has found good evidence that HCQ reduces Covid-19 mortality significantly. It should be noted that conditions apply.
HCQ has been widely used as a drug to treat malaria and to prevent malaria in travellers to malaria-endemic zones, for decades. Once its anti-inflammatory and immune suppressant properties were identified, it began to be used the world over in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In fact, in developed countries without malaria, it is widely but almost exclusively used by rheumatologists. The side-effect profile has been well characterised and protocols for monitoring side effects are taught in all medical colleges. The drug has withstood the test of time.
When the chikungunya pandemic seeded epidemics in various states in India during 2002 through 2006, many patients in the post-chikungunya-fever phase developed persistent and disabling large joint pain and swelling, lasting months to years. HCQ came to their rescue and physicians have been using it with remarkable success, but with all due precautions.
HCQ in Covid pandemic
The story of HCQ and Covid-19 began in Wuhan, China, where patients who were on HCQ, attending rheumatology clinics, seemed to be relatively protected from serious Covid-19 than those attending other clinics. Looking for possible treatment options, Chinese physicians stumbled on HCQ . So they began using HCQ empirically for treating Covid-19.
French physicians, familiar with HCQ used against an endemic bacterial disease called Q fever, followed up with scientific studies for seeking objective evidence for HCQ use in Covid-19. There was laboratory evidence that HCQ acts against SARS coronavirus type 1 and, more recently, also against type 2 that causes Covid-19. The French reported that HCQ reduced both the viral load and duration of virus shedding in the upper respiratory tract of Covid-19 patients. That paved the way for global use of the drug for Covid-19, with believers and sceptics raising a cacophony of controversies. Adding fuel to the fire, indiscriminate use without due precautions, over-dosing, and prolonged usage resulted in many adverse side effects described in the books, even deaths. So the pendulum swung away from its use in many countries.
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In the US, rheumatologists were unhappy because of shortage of HCQ for the legitimate needs of their patients, on account of heavy demand for the drug to prevent and treat Covid-19 — based more on empiricism than evidence. India, the world’s largest producer of HCQ, exported huge supplies of the drug to the US and Brazil in April.
There was a widespread clamour for controlled clinical trials. There was the Recovery trial in the UK and the Veterans Administration trial in the US, both on seriously ill Covid-19 patients. HCQ did not reduce mortality and the pendulum swung against HCQ use in Covid-19. The World Health Organization (WHO) had the Solidarity trial with HCQ in one arm. A scientific paper on a large number of patients, published in The Lancet, reported an unacceptable frequency of serious HCQ side-effects, based on which WHO hastily withdrew it from the study. Within days, it became evident that the Lancet article was based on doubtful data and the journal withdrew the article with alacrity. Immediately WHO made a volte face and re-introduced HCQ in the Solidarity trial, only to withdraw it soon after the UK Recovery trial showed lack of benefits with the drug.
The Detroit study on Covid-19 patients aged 18 to 76, the majority with co-morbidities, was protocol-driven. In one group a short course of HCQ was started early, preferably on the first or latest second day of hospitalisation. In order to avoid serious side effects, the drug regimen was short – 400 mg twice on day one, followed by 200 mg twice daily for four more days. Corticosteroids were used as adjunct therapy in a proportion of patients in both groups. The in-hospital mortality for Covid-19 was 26.4 per cent in those not given HCQ, reduced to 13.5 per cent in the HCQ-treated group.
The Detroit study has swung the pendulum all the way back, favourable to HCQ use in Covid-19. If the scientific evidence from France was for reduction of viral load in the upper respiratory tract, was it not likely that it reflected a reduction of viral load in all other infected body tissues also? When should the viral load be reduced – late in the course of disease or early? Does it not make sense to use the drug early and not late?
The road ahead
HCQ is obviously not a panacea for severe cases of Covid-19. Given early, it helps reduce mortality by about half, compared to those not given HCQ. In India the drug is widely available and not expensive. A number of Indian states have already incorporated a short course of HCQ in their Covid-19 treatment protocol, and states that have not done so will do well to implement this quickly.
Two other therapies for mortality reduction are a short course of dexamethasone and convalescent plasma. Indian physicians have a golden opportunity to use the three modalities in sequence – dexamethasone in those who do not improve with early use of HCQ and convalescent plasma for those who do not improve with dexamethasone. The outcome of this treatment sequence will inform the medical community how to save many lives.
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Dr Seshadri is retired Professor of medical endocrinology, Christian Medical College, Vellore and currently Director, Thirumalai Mission Hospital Ranipet. Dr John is retired Professor of Clinical Virology, CMC, Vellore and Past President of Indian Academy of Pediatrics.