A woman holds a hydroxychloroquine prescription in Seattle, Washington, March 31, 2020. Photo: Lindsey Wasson/Reuters
- ICMR has, at long last, removed ivermectin and hydroxychloroquine from its COVID-19 treatment guidelines.
- The support for these drugs to treat COVID-19 has been hard to explain, at least in scientific terms, given the near-complete lack of evidence.
- India’s sustained support for hydroxychloroquine in particular was partly rooted in political interests.
On September 23, India’s apex medical research body, the Indian Council of Medical Research (ICMR), revised its ‘Clinical Guidelines’ for COVID-19. Specifically, it removed mention of two drugs that a panoply of experts and non-experts had widely used and promoted both in India and worldwide, and which had also been ceaseless sources of controversy: ivermectin and hydroxychloroquine (HCQ).
The previous version of the national COVID-19 treatment protocols, dated May 17, 2021 (the one from which ICMR dropped the use of convalescent plasma) suggested that ivermectin and HCQ “may” be used despite “a low certainty of the evidence”. This feeble cautionary note did nothing to dampen the ill-founded enthusiasm for the use and promotion of both drugs.
With the new revision, ICMR – and India – are now in line with accepted good practice vis-à-vis managing COVID-19, at least on the count of these two drugs. The guidelines of the US National Institutes of Health, the UK National Institute of Health and Clinical Excellence (NICE), and the WHO all negatively recommend ivermectin and HCQ.
In addition, both the US Food and Drug Administration (FDA) and the European Medicines Agency have said that ivermectin is not an antiviral drug, much less an anti-COVID drug.
But within India, the consensus hasn’t been so well-defined, and the official treatment recommendations themselves have been polarising. India Today reported as far back as June 7 that the Directorate General of Health Services, a body under the Union health ministry, had dropped ivermectin and doxycycline – a broad-spectrum antibiotic – from its recommendation. But some news reports also suggested that Indian government experts and advisers were still debating among themselves as to whether ivermectin should be used.
This may explain why ICMR took so long to come around and exclude ivermectin from the guidelines – more so since it is well-known today that ICMR also deferred to political interests through the length of the pandemic.
The fascination with and support for ivermectin as a prophylactic agent against COVID-19 is hard to explain.
Ivermectin’s proponents through the pandemic have made many dubious claims about what the drug can do – but what it can really, actually do is worth remembering.
William Campbell and Satoshi Omura won a part of the Nobel Prize for medicine in 2015 for, among other things, discovering ivermectin in 1975. It became available for human use just six years later, in 1981. Campbell and Omura developed it as a cure for a number of parasitic infections in animals. In their citation, the prize-giving committee wrote, “The importance of ivermectin for improving the health and wellbeing of millions of individuals with river blindness and lymphatic filariasis, primarily in the poorest regions of the world, is immeasurable.”
Ivermectin came to the attention of COVID-19 researchers when scientists published a paper in November 2020 (preprint here) suggesting its potential to benefit hamsters infected with the novel coronavirus in laboratory conditions. Going from lab hamsters to real-world humans is a big leap, but healthcare workers widely adopted ivermectin in many parts of the world without waiting for larger, more informative studies.
Then, by the time such studies did happen and found no reason to think ivermectin could help defend against COVID-19, the drug’s proponents simply dismissed the results. In fact the strength of opinion and conviction that ivermectin could be a panacea against COVID-19 seems inexplicable, at least in terms of the science. Fortunately, there is now a wealth of reliable clinical studies, numerous research reports and systematic reviews that show one thing and one thing only: zero evidence that ivermectin works against the disease.
In June 2021, a systematic review and meta-analysis of clinical trials of ivermectin, published in the journal Clinical Infectious Diseases, concluded: “Ivermectin did not reduce all-cause mortality, length of [hospital] stay or viral clearance in [randomised controlled trials] in patients with mostly mild COVID-19. Ivermectin did not have an effect on adverse effects or severe adverse effects and is not a viable option to treat patients with COVID-19.”
Yet there still seems to be an international movement of sorts that is set on ‘proving’ that ivermectin works. The principal effort comes from a group calling itself ‘Frontline COVID-19 Critical Care Alliance’ (FLCCC); it still has on its website a paper its members submitted to a journal called Frontiers in Pharmacology, which “provisionally accepted” the paper before removing it in March 2021.
Ivermectin-for-COVID theories have also enjoyed political support of sorts, mainly from self-appointed experts in elected positions and with a large number of followers on social media platforms. One such is the Australian Labour MP Craig Kelly, who recently blamed “Big Pharma, Big Govt, health bureaucrats & [mainstream media]” for sidelining ivermectin, and Australia’s key to greatness with it.
Overall, there lingers in pockets of the world a concerted effort to manufacture and/or twist the available scientific evidence in favour of ivermectin, even if science breaks in the process. The drug has become a martyr in the eyes of conspiracy theorists, who continue to broadcast their claims on social media and by uploading dubious research papers and review articles to the web.
It takes considerable effort and expertise to show that studies claiming a benefit with ivermectin are methodologically flawed and misleading. This is also why, though it has taken time, it is gratifying that ICMR has finally fallen in line.
The story of India’s blind faith in HCQ is best reflected in the infamous, and more sensational, Rigano-Todaro paper.
On March 13, 2020, Greg Rigano and James Todaro, two cryptocurrency investors – by no means medical experts – publicised a seemingly innocuous idea through a public document, about the antimalarial drug chloroquine. Three days later, rockstar entrepreneur Elon Musk found the document and tweeted encouraging about it to his 60 million followers: “Maybe worth considering chloroquine for C19”. A day later, Musk replied to his own tweet with three equally damaging words: “Hydroxychloroquine probably better”.
These hapless claims soon caught the attention of then US President Donald Trump. In early April 2020, Trump upped the ante and fired off a personal request to India’s Prime Minister Narendra Modi – to lift an export ban on HCQ manufactured in India. Trump reportedly cited good relations with India, and with Modi personally, but also warned of “retaliation” if India attempted to block exports in any way.
This was of course grist to the mill of the populist, but not entirely ill-founded, trope of India as the world’s pharmacy. Trump was figuratively begging his best friend Modi to release HCQ supplies to the mighty USA, and Modi obligingly tweeted his support while his office released an obsequious press release emphasising Modi’s apparent clout.
However, by June 2020, the US FDA revoked its authorisation for hydroxychloroquine as a treatment for COVID-19, for safety reasons. But support for its use continued to grow, with many ascribing India’s relatively low official – but undercounted – case numbers to the use of HCQ and ivermectin.
And just as with ivermectin, systematic reviews and meta-analyses ultimately found that HCQ was never the silver-bullet many said it was – although not before the drug’s widespread use caused great harm. As one editorial by the influential Cochrane Library put it in March this year:
“The dissemination of information on these drugs in the scientific press and other media has been rapid and tumultuous with strong and polarised opinions among scientists, politicians, and the general public, building a climate of mistrust. Potential resulting harms included wasted resources (including research capacity) and drug shortages for evidence‐based indications. The false hope instilled may have also led to unsupervised use of potentially harmful medications.”
Even if they are not binding, clinical guidelines from official bodies are vitally important for healthcare workers in the ‘field’. They summarise the available evidence and make clear recommendations about which drugs to choose and which mode of treatment to prioritise in common yet different circumstances. For too long, India has lacked an official authoritative and independent clinical advisory body with the expertise, resources and the academic clout to get these guidelines right, and on time. The COVID-19 pandemic sorely tested this system, and found it deficient.
ICMR may not be best placed to undertake this important task. In the pandemic’s early days, it seemed to walk on eggshells, often skirting around or avoiding questions about differences between its opinions and global scientific findings. More recently, concerns about its independence were validated by reports in the New York Times and The Lancet that laid bare its failure to separate its scientific and editorial responsibilities from the needs of its political masters.
The delay in official advice to stop chasing after ineffective and potentially harmful remedies is also symptomatic of the general lack of scientific temper, reasonable scepticism and, honestly, some spine precisely where we need them most: our scientific institutions. And this is even before we consider the more serious issue of a Union ministry with money and license to promote unscientific, untested, unproven traditional remedies from the realm of Ayurveda as cures for COVID-19.
It is by now a cliché to say the COVID-19 pandemic showed up, and continues to show up, the lack of depth in India’s science establishment. But it is a cliché worth repeating because we have become a people adept at forgetting. Fleeting achievements in vaccine-manufacturing and laboratory testing will always remain flashes in the pan unless we invest more to develop a culture of scientific enquiry, interrogation, civil disagreement and independence that also doesn’t crack under the slightest pressure.
In the limited context of clinical-guideline development, India needs to invest in clinical epidemiology expertise, statisticians, clinical-trial experts, librarians and scientists trained at critically appraising research and conducting meta-analyses and systematic reviews. The importance of these exercises for India specifically is that their broad-based nature represents the most effective way to offset – both politically and scientifically – the cult of personality that has overtaken the country.
And until recently, it would seem, ivermectin and HCQ were similar personalities, embodying the paranoia of conspiracists as much as the delusions of nationalists.
Dr Jammi Nagaraj Rao is a public health physician, independent researcher and epidemiologist in the UK.