What we do have by now is fairly sound but not entirely irrefutable evidence that the anti-malarial drug has no therapeutic effects on people infected by the novel coronavirus.
On the contrary, a recent observational study – the largest of its kind – published in the renowned medical journal, The Lancet offers cause for concern. Based on the records of nearly 15,000 patients who were administered the drug and 81,000 who were not, the study showed that the former group was, actually, more likely to develop heart-related complications and die.
The study confirmed what several studies employing various research methodologies had earlier suggested: that there is scant data to conclude with certainty that hydroxychloroquine is effective in treating Covid-19 in living beings even though it had shown early promise in laboratory studies.
The Lancet study had immediate repercussions: the World Health Organisation “temporarily suspended” trials of the drug, citing safety concerns.
An endorsement without evidence
Yet, on May 22, the same day as the Lancet study appeared, the Indian Council of Medical Research, the apex medical research body spearheading the country’s response to the pandemic, expanded the usage of the drug as a preventive medicine for Covid-19.
While the drug was earlier recommended for “asymptomatic healthcare workers involved in the care of suspected or confirmed cases of COVID-19” and “asymptomatic household contacts of laboratory confirmed cases”, the ICMR in the new amendment included frontline workers such as the police.
Justifying its decision, the ICMR cited three ongoing indigenous observational studies, which purportedly showed that Indian healthcare workers who had taken the drug, as per its previous advisory were less likely to contract the disease.
None of these studies, however, are randomised controlled trials – the gold standard of clinical trials. In randomised controlled trial studies, a group of people who are administered a clinical intervention are compared to others who receive a placebo or no intervention at all.
That apart, the ICMR has not made much information about these studies public: the protocols used, monitoring strategies adopted, toxicity assessments done and more.
It is not surprising then that the ICMR’s decision to not only continue but expand the use of hydroxychloroquine, seemingly in contradiction of available evidence, has come under scrutiny.
Steadfast ICMR, sceptical doctors
However, the medical body has held its ground. Rajni Kant Srivastava, a senior scientist at the council, told the news website The Print that the much-cited Lancet study discussed the drug’s therapeutic effects and not its prophylactic properties that the ICMR endorsed.
While that is true, several experts pointed out that there has been no credible study on the prophylactic effects of the drug at all. “While it is now clear that HCQ doesn’t help in treatment and is on the contrary perhaps even harmful, there is simply no data on its prophylactic values,” said Amar Jessani, a physician and medical ethics researcher. “The ICMR is talking about observational studies it has done, but where is the data?”
For many others, the Lancet study was a clear red flag for prophylactic use, regardless. “Preventive drugs have to be even safer than treatment ones,” said Yogesh Jain, a public health physician at Jan Swasthya Sahyog in Chhattisgarh’s Bilaspur. “I may use a possibly toxic drug as the last recourse for someone who is morbidly sick, but never for someone who is not sick.”
Show me the research
As Jessani pointed out, there are few credible published studies on the prophylactic effects of hydroxychloroquine – though there are a few in progress.
In a recent correspondence to Lancet supporting the IMCR’s endorsement of the drug as a preventive medicine, four doctors from the All India Institute of Medical Science’s department of medicine, cited a completed study from South Korea as evidence of efficacy of hydroxychloroquine for post-exposure prophylaxis. The four doctors, led by the senior AIIMS physician Manish Soneja, were responding to another correspondence that questioned the ICMR’s rationale.
However, on a closer reading of the South Korean study, the claim of Soneja and his associates does not quite hold up. While health care workers who received the drug did not contract the virus, neither did the ones who did not. “We could not conclude that…[hydroxychloroquine] is effective for prevention of COVID-19 in close contacts,” the authors of the South Korean study acknowledged, adding that randomised clinical studies are needed to evaluate the efficacy of the drug as a preventive medicine.
Regardless, this study was published on April 17 – almost a month after ICMR issued its first advisory recommending the use of the drug among health care workers and close contacts of infected people.
While the AIIMS doctors’ letter to Lancet was an independent intervention – the authors declare no conflict of interest – it is perhaps the closest to an academic defence of the Indian health administration’s position on the data.
On Tuesday, the ICMR chief Balram Bhargava seemed to borrow some of the language of the correspondence to articulate India’s position on the drug. “Looking at the risk benefit...we should not deny our frontline workers and healthcare workers who are going to be dealing with the patients of Covid and can get some treatment,” said Bhargava at the media briefing on the coronavirus situation in India, mirroring the AIIMS correspondence.
But many doctors and public health experts said this seeming endorsement of hydroxychloroquine by ICMR could lead to indiscriminate consumption of the drug, particularly now that the drug had been greenlighted for even frontline workers such as the police.
Reckless use of the drug was inevitable, said Jain, even though the ICMR advisory explicitly cautioned against harbouring “a false sense of security” while consuming it. “An ICMR advisory comes with the sanctity of having come from the top medical research body of the country,” said Jain. “With power like that comes responsibility, but the ICMR has not followed any due process in recommending HCQ for prophylactic use.”
Another doctor at AIIMS, who did not want to be identified, agreed. “Even if we were to go by the logic that it causes no harm or benefit, there is a chance of many seeing it as a wonder drug,” said the doctor. “Which may lead to people actually not following what definitely prevents the disease: social distancing, washing hands, wearing masks.”
To add to all of that, concerns about side effects of the drug also persist despite the ICMR playing them down. “It should be continued because there is no harm, benefit may be there,” Bhargava said in the media briefing.
In its latest advisory, the ICMR said that it had assessed data of 1,323 health care workers who had received the drug and found that its side effects were minor to non-existent. However, it conceded that the data from India’s pharmacovigilance programme revealed 214 reported instances of adverse drug reactions. Three of them exhibited irregularities in their heart beats. Reports, though, suggest that the pharmacovigilance program could be undercounting adverse effects owing to lack of reporting by hospitals.
Hydroxychloroquine could cause arrhythmia – irregular beating of the heart, either too fast or too slow – which could ultimately lead to cardiac arrest.
The ICMR has accounted for some of these concerns in its latest advisory. It has called for the screening of people with certain conditions that could make them more vulnerable to the drug’s side effects and also made an electrocardiogram mandatory during the course of the prophylaxis – an ECG can pick up signs of a heart attack or any other heart-related irregularities.
The AIIMS correspondence also happened to share a similar view as the ICMR – though perhaps even more militant – about the side-effects of the drugs being too minimal to be a deal breaker. It accused the original correspondence it was responding to of causing “unjustified alarm” for expressing concerns side effects of the drug
However, the authors of the latter said they stood by their contentions. “The side effects are well known, and are usually mild. However, when tens of thousands of people take a drug, even the rare side effects matter,” said the authors of the paper in an email to Scroll.in. “And we do not know how many would experience severe side effects.”
All prospects of a serious study scuttled?
These questions, experts say, can only be settled by a randomised controlled trial. However, the ICMR said it was difficult to carry one out. Private institutions in India have also struggled to execute them. Such studies require a control arm comprising people who have not had the drug. But as healthcare workers are reluctant to participate and to decline taking the drug .
Jessani said the ICMR was squarely to blame for this research crisis. He said, “First you declare that a drug is beneficial without any kind of evidence, then you say you cannot do an RCT to find out if it is actually beneficial because you can’t deny people of the benefit – but no one knows what that benefit is.
“I never thought science in India would be reduced to such a sorry state,” added Jessani.