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Hydroxychloroquine: An Angels And Demons’ Story

May 1, 2020

Hydroxychloroquine (HCQ) have been used for various rheumatological disorders (RMD) by millions of people around the world for many decades without much fuss.

But in March 2020, hydroxychloroquine was made a hero as it was advocated for prevention and treatment of COVID-19 infection.

As the world was preparing to fight the new pandemic using HCQ, there came reports of sudden death with its use and this shook the world of rheumatology.

On March 21, the US President Donald Trump in a press conference promoted hydroxychloroquine to treat COVID-19.

"The combination of HCQ and azithromycin has a real chance to be one of the biggest game-changers in the history of medicine," Trump had further tweeted.

This led to a sell of HCQ so much that pharmacies worldwide started reporting shortages within 24 hours.

Development of hydroxychloroquine

In 1891, Paul Ehrlich and colleagues found that methylene blue was effective against malaria. The methyl group was replaced with a basic side chain to make pamaquine.

Further modifications led to the formation of many antimalarial drugs among which resochin and its further modification, chloroquine (CHQ), were widely used for the treatment and prevention of malaria.

Along with antimalarial effect, beneficial effects of CHQ was also observed on various skin disorders and arthritis. Later on, modification of CHQ molecule led to the development of HCQ, with 1/3rd toxicity of CHQ.

Since then, HCQ has been adopted for most of the non-malarial and chronic indications.

Hydroxychloroquine in rheumatology and dermatology

HCQ is used in systemic lupus erythematosus (SLE), discoid lupus, rheumatoid arthritis (RA), Sjogren’s syndrome, dermatomyositis, sarcoidosis etc and skin diseases like porphyria cutanea tarda.

One of the pivotal studies in 1990 showed that if we stop HCQ in SLE patients, the disease comes back.

Afterwards, many studies confirmed that HCQ substantially reduces disease activity, flare up and death in SLE.

Therefore, patients with SLE should not stop HCQ at any point unless advised by a rheumatologist.

HCQ in heart disease

Atherosclerosis causes heart attack, stroke etc. Rheumatological diseases accelerate atherosclerosis and contribute to a higher heart attack and stroke burden in these populations.

Reduced incidence of heart attack, stroke and death from all-cause is seen with hydroxychloroquine because of its multiple effects.

HCQ lower the incidence of increased blood pressure and has a significant effect on insulin sensitivity, lipids, and reductions in fasting sugar. Some reports show an increase in HDL levels.

HCQ in Kidney disease

HCQ in SLE reduces the incidence of kidney disease. It decreases the chance of kidney failure in SLE and RA. HCQ significantly reduces leakage of protein in urine in IgA nephropathy.

HCQ & CHQ and cancer

Interest is on the use of HCQ in many tumours after it was observed that the incidence of Burkitt’s lymphoma was low in countries where CHQ was widely distributed for malaria.

HCQ and CHQ for COVID-19

The antiviral effects of chloroquine were described in a research paper published in The Lancet in 2003.

Both CHQ and HCQ were shown to inhibit SARS-CoV-2 in a lab setting by inhibiting their entry and multiplication.

However clinical study with HCQ and CHQ in viral diseases including COVID-19 is very limited.

One small study from France demonstrated benefit but had serious methodological flaws, and a follow-up study still lacked a control group.

Another study from China in patients with mild to moderate COVID-19 found no difference in recovery rate.

We have to wait for a few weeks for the result of a few studies on HCQ; e.g. HCQ is currently administered to 1,100 COVID-19 patients in New York- the result is awaited.

Toxicity of hydroxychloroquine

HCQ is one of the safest drugs with good long-term tolerance in general and special populations like pregnant individuals and those with kidney failure.

The abdominal problem, the effect on eyesight (retinopathy), darkening of skin and other skin reactions, muscle weakness, and blood complications are the most relevant adverse effects.

Retinopathy is the most noticeable adverse effect. At doses of 4–5 mg/kg/day, the risk of retinopathy with 10 years of therapy is < 2 per cent and increases to > 20 per cent if used > 20 years.

Apart from the darkening of the skin, other adverse events are very rare. Cases of decrease in haemoglobin among those with genetic G6PD deficiency has been reported.

HCQ and QT prolongation

QT prolongation is a risk factor for an irregular heartbeat which may lead to even death if not recognized early.

QT prolongation has been observed in some people who are using HCQ to prevent or treat COVID-19.

They were used along with other drugs or risk factors for QT prolongation. In SLE on the other hand, QT was significantly higher with high disease activity and HCQ and CHQ has found to be protective.

Though in the long-term HCQ is one of the safest medicines, HCQ must not be used for prevention or treatment of COVID 19 without medical supervision.

Hydroxychloroquine shortage

The evidence for the use of antimalarial for prevention and treatment of COVID-19 is equivocal, but for rheumatological diseases is robust. Patients with rheumatological disorders taking HCQ should not suffer because of the shortage of it because of inadvertent use or hoarding for COVID 19.

Every stakeholder should coordinate an aggressive response to ensure that antimalarial drug use is appropriate.  One silver lining is, brief gaps of HCQ for 1 - 2 weeks should be less concerning in long-term use as the half-life is 40-50 days. Longer treatment lapses increase the risk of disease exacerbation.

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