A researcher works with coronavirus samples as a trial begins to see whether hydroxychloroquine can prevent or reduce the severity of COVID-19, at the University of Minnesota. Photo: Reuters/Craig Lassig.
Note: On May 4, 2020, the Indian Council of Medical Research registered a hydroxychloroquine trial for its use as a prophylactic drug on the Clinical Trial Registry of India. This followed extensive reporting on the issue by Priyanka Pulla for The Wire Science, including the following article.
On March 29, a few days after he took an antimalarial drug called hydroxychloroquine, Anand Acharya (name changed), a 44-year-old doctor in Guwahati, began feeling unwell. A WhatsApp message that his colleagues said he sent that afternoon suggested he blamed the drug. It read, “HCQS [short for hydroxychloroquine sulphate] is not very good as prophylaxis. Lots of issues. I’m having some problems after I took it.”
Acharya was among many doctors across India who began taking hydroxychloroquine recently to stave off COVID-19, the viral illness that has killed over 55,000 people around the world thus far. He was an anaesthesiologist whose job – among other things – would have been to insert tubes into the windpipes of COVID-19 patients who needed help breathing. This procedure can throw a fine cloud of viral particles into the air, putting anaesthesiologists at especially high risk of contracting the disease.
For such healthcare workers, India’s apex medical research agency, the Indian Council of Medical Research (ICMR), has been recommending the use of hydroxychloroquine as a prophylactic against COVID-19 since March this year.
Within hours of sending the ominous WhatsApp message, Acharya collapsed. He was rushed to Guwahati’s GNRC Hospital, where cardiologist Biplab Paul tried to revive him. His attempts failed: by around 2:30 pm, Acharya had passed away. Paul said the death was due to sudden a cardiac arrest: the heart had stopped pumping blood to the rest of the body.
The doctor’s unexpected death has raised questions about the pitfalls of India’s policy to use hydroxychloroquine – an unproven drug – as prophylaxis for healthcare workers and household contacts of COVID-19 patients. The evidence in this antimalarial drug’s favour is scant, and the drug isn’t without risks either. Patients who have been taking hydroxychloroquine for years sometimes suffer damage to the eye’s retina or abnormalities in the heart’s electrical system.
On March 29 – the same day Acharya sent his WhatsApp message – the American College of Cardiology said in a statement that given the adverse effects of hydroxychloroquine, those taking the drug should either do so as part of a clinical trial or only after evaluating its risk and benefit together. A few days later, a review article in the American Journal of Tropical Medicine and Hygiene emphasised the need for care when taking hydroxychloroquine.
The Kolkata-based cardiologist Rabin Chakraborty, who is also president-elect of the Indian College of Cardiology, agreed with this approach. “I would advise a tremendous degree of caution while taking hydroxychloroquine,” he told The Wire Science. “Be judicious, apply wisdom, and take advice from medical professionals, preferably a cardiologist.”
This isn’t happening everywhere in India. Hospitals and state governments around the country have been implementing ICMR’s recommendations in different ways. For example, healthcare workers in Rajasthan and Bihar were given the drug without screening for risk-factors, officials from the Integrated Disease Surveillance Programme in both states said.
In Bhilwara, a district with a cluster of 27 confirmed COVID-19 cases, some 200 doctors and 500 nurses have received the drug so far, according to Ghanshyam Chawla, the deputy chief medical and health officer of the district. He added that it was not necessary to screen them and that no one had reported adverse effects, at least not yet. “Even paracetamol has some side effects but we don’t screen people taking it. Hydroxychloroquine is the same,” Chawla told The Wire Science.
In contrast, a doctor from a Kerala government medical college (who didn’t wish to be named) said the hospital was evaluating all individuals taking the drug for risks. Such screening included administering an electrocardiogram (ECG) in certain patients to look for heart-related electrical abnormalities. These abnormalities can exacerbate hydroxychloroquine’s ill-effects on the body, he said.
Kavitha Saravu, head of the infectious-disease department at the Kasturba Medical College, Manipal, also told The Wire Science that all healthcare workers at the hospital had to get a prescription from a doctor before taking hydroxychloroquine.
Apart from hospitals and state governments implementing ICMR’s policy, many individual doctors are also popping the drug on their own. For example, even though the Guwahati hospital where Anand Acharya worked was not supplying hydroxychloroquine to all healthcare workers, the medical superintendent told me workers had begun taking the drug by themselves after the ICMR’s guidelines were out. The Wire Science also heard two audio recordings in Malayalam being forwarded on WhatsApp, exhorting all doctors to take tablets of the drug. Both messages implied – wrongly – that hydroxychloroquine’s benefits were clear and that there were no risks.
If thousands of Indian healthcare workers start taking the drug, experts say even rare side-effects could show up widely. This is why it is critical for India to investigate any reports of serious adverse events, such as deaths, linked to the drug. The ICMR guidelines clearly ask that such events be reported to the Pharmacovigilance Programme of India (PvPI), which is run by the India Pharmacopoeia Commission.
However, The Wire Science was not able to ascertain if PvPI was investigating the death of Anand Acharya or, for that matter, other potential reports of adverse effects after the large-scale administration of hydroxychloroquine began. Questions sent to the scientific director of the Indian Pharmacopoeia Commission, Jai Prakash, went unanswered. The Wire Science will update this story as and when he replies.
What little we know
Many gaps exist in our understanding of if and how hydroxychloroquine works against COVID-19. Most of the favourable data comes from studies in Petri dishes. There have been a handful of human studies (such as this, this and this), some of which examined hydroxychloroquine and azithromycin together as potential treatment. But their results have been conflicting. And none of them evaluated hydroxychloroquine as a prophylaxis for COVID-19, which is a different ball-game altogether.
Petri dish research can make both hydroxychloroquine and the structurally related chloroquine look better than they really are. This has happened before. Both anti-malarial drugs inhibit the Ebola virus, the influenza virus, chikungunya, dengue and HIV in human and animal cells grown in controlled conditions in the laboratory. However, clinical trials – which involve giving the drug to humans and animals – have failed to confirm the drugs’ efficacy. In fact, despite all the promising evidence of hydroxychloroquine’s antiviral effects in in vitro studies, no regulator has ever approved it for any viral disease.
Some scientists also worry that hydroxychloroquine could make healthy people more vulnerable to COVID-19 – which is the opposite of what ICMR intends. The drug blocks the production of a molecule called interferon alpha, which is a key part of the body’s defence against viruses. In doing so, it could hamstring a person’s ability to fight off COVID-19, said Art Krieg, a former practicing rheumatologist and the founder of Checkmate Pharmaceuticals, a US-based firm that studies cancer immunotherapies.
Paradoxically, the same behaviour of hydroxychloroquine could help sicker COVID-19 patients because many of them suffer from an overzealous immune response1 that ravages their bodies. Here, tamping down the immune response may actually help patients recover.
This key difference in the drug’s impact during the early stages of the disease and later make it a bad idea for people who are not already sick, Krieg said. “I would not take HCQ myself to prevent COVID-19 nor would I recommend it to any friends,” he told The Wire Science over email.
Still, the favourable results of Petri-dish studies on hydroxychloroquine mean that several clinical trials for its use as a prophylactic are already underway. The good news is there are indications that the drug works at doses currently approved for people with malaria, lupus or rheumatoid arthritis. This is helpful because the adverse effects linked to these doses are fairly well understood. For example, rheumatologists who prescribe hydroxychloroquine to patients with lupus already know that it can damage the retina or trigger heart conduction abnormalities in some of them.
And both these conditions – while causes for concern – tend to occur after many years of sustained use. Heart abnormalities are also particularly rare, according to Debashish Danda, a rheumatologist at the Christian Medical College, Vellore. This is again cause for comfort because ICMR’s prophylactic schedule goes on for only seven weeks. So these side-effects are not very likely to appear.
There is a problem, however: the dose that ICMR has recommended lies towards the higher end of the spectrum that rheumatologists prescribe. While most patients receive a maximum of 400 mg of hydroxychloroquine in a day, ICMR’s suggested dosing schedule starts with two 400 mg doses on the first day. Afterwards, the dose is lowered to 400 mg per week. The idea of the first double dose – called a loading dose – is to quickly build up the requisite level of hydroxychloroquine in the body.
This loading dose worries Danda a little. “I don’t know if someone who has a background cardiac illness would be more at risk with such a dose. So I won’t recommend that people use it left, right and centre.”
The heart and hydroxychloroquine
The cardiac side-effect of hydroxychloroquine that Danda and others are thinking about is called long-QT syndrome. The electrical signal that contracts the heart muscles, thus allowing them to pump blood, passes through the heart once every heartbeat and shows up on an ECG as a series of waves labelled P,Q, R, S and T. When the time delay between the Q and T waves becomes longer than it should be, the condition is called long QT syndrome. This syndrome can render the heart beat chaotic in some people. This arrhythmia can in turn lead to a sudden cardiac arrest – of the kind that killed Acharya.
Many drugs can prolong the QT interval, including bedaquiline, which has been gaining in prominence in the fight against tuberculosis, and the antibiotic azithromycin. Even some genetic mutations can cause it, according to Chakraborty. Unfortunately, those with the syndrome often don’t know it because they may not experience any symptoms. When the cause is a genetic mutation, the only red flag for people carrying the mutation could be a history of sudden cardiac arrests in the family.
For this group of people, hydroxychloroquine would be dangerous, Chakraborty said. “My suggestion for anyone taking the drug would be to get a prescription from a doctor. The patient should have had a previous ECG, and the patient should have no history of sudden death in the family.”
It is unclear whether Acharya had any risk factors like long QT syndrome that made him vulnerable. His colleagues said he had hypertension, and some drugs used to treat hypertension can lengthen the QT interval. But without getting into Acharya’s health history, it is impossible to say if his death was related to hydroxychloroquine, Paul – the cardiologist who attended to him before he died – said.
ICMR has not responded to questions about whether it has initiated an investigation. However, the agency’s chief of epidemiology, Raman Gangakhedkar, said in a press conference that it was unlikely that the Guwahati doctor’s death was due to hydroxychloroquine because he had not taken the drug for a long enough time.
Pandemics and prophylaxis
The decision to give a healthy population an unproven prophylactic drug in a pandemic is controversial. Some have said it is justified because doctors and nurses are at high risk of contracting the new coronavirus and there is no time to wait for the results of clinical trials.
T.R. Raghu, a cardiologist at the Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, who has himself taken the drug, belongs to this camp. “A pandemic is a medical emergency. We don’t have the time to do a placebo-controlled clinical trial right now,” he said. The fact that his hospital has conducted ECGs in hundreds of lupus and rheumatic arthritis patients and not detected long-QT-syndrome gives him more confidence.
But he agreed that although rare, the QT interval can be prolonged. According to one 2013 case report, a 41-year-old New York woman suffering from lupus, high blood pressure and chronic kidney disease experienced dangerous QT-prolongation soon after taking hydroxychloroquine. Then, last week, another study from New York found that of 80 COVID-19 patients being treated with a combination of azithromycin and hydroxychloroquine, 11% experienced an increased QT interval (to more than 500 ms) linked to potentially fatal arrhythmias.
Incidentally, ICMR has also recommended this combination to treat severely ill COVID-19 patients in India, again on the basis of scant evidence.
Meanwhile, it’s clear that India’s vote of confidence in the drug has precipitated a spike in consumption. Danda and other rheumatologists said their patients are unable to find it in stores. To tackle these shortages, Indian authorities have announced an export ban and told manufacturers to be ready to increase production.
One reason healthcare workers are taking the drug so enthusiastically could be the shortage of personal protective equipment (PPE), like masks and gloves, in hospitals across the country. “We do not have enough PPE, so hospital staff are taking the drug for fear of getting infection,” Subhash Khanna, a laparoscopic surgeon in Guwahati, said. Khanna and his family of doctors had all purchased hydroxychloroquine soon after ICMR released its guidelines – but changed their minds after Acharya died.
How dangerous can the widespread use of hydroxychloroquine be? Chakraborty said he really didn’t know. Only when the results of randomised clinical trials are out can anyone begin to understand the drug’s risk-benefit ratio. But the cardiologist is worried that the fear of COVID-19 could make some people swallow a drug that is deadlier for them than the disease itself. “We don’t want to jump out of the frying pan into the fire. That’s all I am saying.”
This article was originally published on April 6, 2020.
Priyanka Pulla is a science writer.
The reporting for this story was funded by a public health journalism grant to Priyanka Pulla from The Thakur Family Foundation.
Known as a cytokine storm↩