A pack of Hydroxychloroquine Sulfate medication | Photographer: John Phillips | Bloomberg
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New Delhi: The Indian Council of Medical Research (ICMR)’s advisory on the usage of anti-malarial drug hydroxychloroquine (HCQ) as a preventive drug created a row last week, with a Lancet study seemingly contradicting its position. But there is a clear and nuanced distinction in the scope between the two.

On 22 May, a study published in the medical journal said HCQ increases the chances of death and irregular heart rhythm. Titled Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, the study was conducted on over 96,000 hospitalised Covid-19 patients across six continents.

On the same day, India’s apex research body released an advisory to expand the usage of HCQ as a preventive drug, or prophylaxis, for Covid-19. This was based on three observational studies the research body has conducted.

But unlike The Lancet study, the ICMR only investigated if frontline healthcare workers, who were given the drug as prophylaxis, contracted the disease or not.

ThePrint analysed the ICMR’s guidelines and The Lancet study to understand how the two studies differ in their scope and what we know of the effects of HCQ on Covid-19.

What The Lancet study found

The Lancet study is the largest observation research to be conducted on the use of HCQ and its predecessor chloroquine as a treatment for Covid-19.

A majority of the previous studies, which spurred the existing perception about the efficacy and safety of HCQ, were small uncontrolled studies.

In India, only five trials have been registered to test the drug’s efficacy and safety, according to ICMR’s Clinical Trial Registry of India (CTRI). Of these, the biggest is the World Health Organization’s Solidarity Trial, with 7,000 participants from across countries. It started recruiting patients earlier this month, according to CTRI.

The Lancet study by four researchers from the US and Switzerland was “a multinational registry analysis” of health records of patients from as many as 671 hospitals from all over the world. 

The analysis included data of the patient’s age, body-mass index, sex, race or ethnicity and their underlying comorbidities. The 96,032 Covid-19 patients who were included in the study had been hospitalised between 20 December 2019 and 14 April. 

Of them, four groups of 14,888 patients received each one of these four treatments —chloroquine, chloroquine with a macrolide (an anti-bacterial drug that works by inhibiting protein synthesis of the pathogen), hydroxychloroquine, and HCQ with a macrolide.

A fifth group served as the control group that received no therapy.  

“When compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%), hydroxychloroquine with a macrolide (23·8%), chloroquine (16·4%), and chloroquine with a macrolide (22·2%) were each independently associated with an increased risk of in-hospital mortality,” the study said. 

Moreover, arrhythmia or irregular heartbeat was observed in only 0.3 per cent of the control group, this was seen in 6.1 per cent of those receiving HCQ, 8.1 per cent of the group receiving HCQ and a macrolide, 6.5 per cent of those being treated with chloroquine and a macrolide and 4.3 per cent of those who were just given chloroquine.

“These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed,” concluded the study.


Also read: Is the R number still useful? It can’t be the sole guide to coronavirus policies


How is it different from ICMR’s studies?

The three studies by ICMR — based on which it put out the advisory Friday — differed in its scope as it only checked if HCQ worked as a preventive drug. 

Of the three, one was an observational study of 334 healthcare workers at New Delhi’s All India Institute of Medical Sciences (AIIMS); a retrospective case control study by ICMR based on previously collected data; and an investigation in three central government hospitals. 

All three indicated that healthcare workers who had taken HCQ were less prone to Covid-19, according to ICMR’s advisory.

The research body, however, has not released data from the studies or made the actual studies public.

The apex health research body also referred to an in-vitro (laboratory) study conducted by the National Institute of Virology in Pune that “showed reduction of infectivity/log reduction in viral RNA copy of SARS-Cov2” (Covid-19’s viral genome).

Multiple in-vitro studies have shown positive effects in fighting the virus in many countries, but there have been no studies confirming that this translates to human bodies yet.


Also read: Chinese vaccine shows promise in early human trial, generates immune response against Covid


‘Protecting, even with side-effects’

Dr Rajnikant Srivastava, head of department of research management, policy planning and communication at the ICMR in New Delhi noted this difference between the international study and the ones by ICMR.

“Day before yesterday (on Friday) we released guidelines based on observational studies only checking the use of HCQ as prophylaxis. For Covid-19 treatment, we don’t have any evidence yet from the WHO Solidarity Trial. Once the clinical trial data comes out only will we be able to say anything,” he said. 

“Even in our observational studies we’ve shown that there are certain side effects, even then it is protecting against Covid-19.

In its guidelines, the ICMR says an electrocardiogram test or ECG test, which checks for the heart rhythms, may be conducted when prescribing the drug, and should be conducted in cases where the individual develops cardiovascular symptoms.

“One ECG should be done anytime during the course of the prophylaxis,” the guidelines say. 

The ICMR guidelines also add that HCQ can be administered only by a medical professional, and informed consent – where the person being given the drug is aware of its side effects – must be sought before administering it. 

‘Won’t change anything without more evidence’

While the US Food and Drug Administration has cautioned against the use of HCQ to treat Covid-19 patients, the treatment guidelines in India state that HCQ and azithromycin, a macrolide, “may be considered as an off-label indication in patients with severe disease and requiring ICU management”. This means that this medication may be used in a manner not specified in the guidelines.

According to ICMR’s Revised Guidelines on Clinical Management of COVID–19, the Covid-19 patient can be administered 400 mg of HCQ for one day and then 200 mg for four days along with 500 mg of azithromycin. 

Asked if the government would reconsider these treatment protocols in view of The Lancet study, Srivastava said, “Unless and until there is more evidence we will not change anything.”

ThePrint also reached AIIMS director Randeep Guleria, who is a member of the National Covid Task Force, through phone calls, but there was no response until the time of publishing this report. 


Also read: Coronavirus isn’t the killer, our immune response is


 

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8 Comments Share Your Views

8 COMMENTS

  1. And the Lancet Paper is retracted and the company is under investigation. their raw data is being questioned by scientific community across the world. Before any non scientific person analyses two scientific paper and writes an article on it, the readers should think twice.

  2. Very Nice article. ICMR article made the point very clear. Chloroquine and hydroxychloroquine are thought to act primarily by 1) altering endosomal pH and thus decreasing virus-cell fusion, and 2) interfering with terminal glycosylation of angiotensin-converting enzyme 2 (ACE-2) receptors, the putative receptor for the entry of SARS-CoV-2 into lower respiratory tract cells}
    When we know the probable pathophysiology of the drug, Lansets study of effectiveness in the Hospital patients doesn’t make sense.

  3. 1. ICMR should stop behaving as a god father for all healthworkers instead it should come out with peer reviewed data on prophylaxis efficacy of HCQ, & let health workers decide for themselves.

    2. There should be proper follow up for doctors who have taken HCQ for relevant cardiac or other side effects. This is even more important as all those taking HCQ are also in high stress COVID duty ( 8-12 hrs duty, hypoxia inducing PPE & stress of safety of family members)….& everything compounds chances of arrhythmia.

    3. Even when the intention of HCQ prophylaxis can’t be questioned, evidences should be paramount in decision making. Otherwise every other drug which is showing in vitro success ( yesterday it was HCQ ,now it is ivermectin) will be taken directly as therapy by the internet physicians of this generation as the highest decision making body is setting the trend.

  4. The ICMR has strongly recommended the healthcare workers to take hydroxychloroquine for prophylaxis WITHOUT any evidence base, and has subjected the healthcare workers to a great risk. Now it is claiming (without a perr-reviewed publication), that a lesser number of those who were taking the drug had infection as compared tk those who weren’t. Doesn’t this amount to a criminal act – research on human subjects without any consent? So ICMR should be sued for two counts of crime – one – recommendation without any evidence base, resulting into at keast to deaths (culpable homicide not amounting to murder), and two – subjecting them to a research without their knowledge.

    • There is so much wrong with your post that it’s almost breathtaking.

      Legally, a medical doctor in nearly all modern nations can prescribe any drug, in their medical opinion that will aid a patient, that has been approved by that nations approving agency. Makes no difference what the “intent” of the drug. Governing agencies mostly certify safety. You’re obviously not a medical doctor or you would know how so-called “off label: medicines therapies work. Oncology, for example, is the biggest “user” of off-label drugs which have been very successful. If you were to practice medicine, you’d know there are all sorts of cons. Dozens of explanatory articles on the subject.

      You should take the skills you developed in researching and discover how observational studies are about 1/2 step above worthless and be able to state the reasons they’re very weak.. That’s why well designed, double blind, clinical trials with definitive outcomes are the “gold” standard. Perr (or maybe peer) review is so corrupt as to be laughable regarding drug efficacy. The best evidence of efficacy other than clinical trials is clinical practice. While researching, look up drugs like thalidomide which passed even clinical trials but in clinical practice were deadly.

      Now consider the safety of HCQ. Literally millions of patient outcomes over decades. Few drugs other than aspirin exhibit a similar record with patients. It’s safe when prescribed by a medical doctor, regardless of “purpose”. The clinical centers that report good results stress the HCQ combo must be given early, preferably at the onset. Lancet used cases without regard to initial treatment – for example, given a dead person (a person on a ventilator) any drug will not be helpful unless your Jesus sitting in Lazarus’ tomb. From the reports I’ve read, there have been more patients successfully treated at the onset of COVID-19 with the HCQ combo than would exist in most drug clinical trials.

      What you should note is the CDC researchers and many other government researchers hold patents on the research (as government employees) of the Moderna vaccine (as would any other government researcher regarding US patents). Perfectly legal under the Bayh-Dole Act (look that up as well). One should follow the money and unearth all the conflicts inside government and the special interests that fund “studies”.

      Obtw, your conjecture of “lethal side effect” begs the question and is a specious statement.. Look those up as well. While your at it, you might want to read something about the la starting with the Model Code of Evidence, maybe even some of the Restatements.

      Even if HCQ is minimally useful, since India has over 75% of the worlds cases of malaria, Millions of Indians and travelers to India have taken HCQ as a preventive. COVID-19 can be a “double” preventative. You seem to wish to infect millions of Indians with both malaria and COVID-19?

      Regarding all their statistics. Clinical HCQ treatment at the onset has successful outcome in the thousands. Observational studies, if honestly conducted with adequate data and allowing for all confounding events (such as when treatment began) would certainly confirm HCQ if administered at the onset. Perhaps, with your degree, you could conduct such a study?

  5. Dear Ms. Chakrabarti, you have analysed and compared both the sides well, but your heading is entirely misleading. This big published study is definitely at odds with ICMR. There are following reasons:
    1. Whatever primary outcome both had intended for, you cannot continue with your recommendation when a lethal side effect has been reported in a multicentric study.
    2. ICMR had recommended this much earlier, even before any publication of prophylactic effect of these drugs, while their side-effects have been well known for ages.
    3. ICMR did not bother to give any cross reference or evidence-base for all its recommendations which reduces them to diktats rather than scientific guidelines. ICMR has to learn and read more international guidelines which carry long discussions and a list of hundreds of references for their recommendations.
    4. ICMR first recommended for HCQ without a study, which was its original job, and led several healthcare workers to take this drug. Then later, it used that data as ‘observational studies’ which are yet to be published in a peed-reviewed journal! This is akin to a criminal misuse of its power, and deliberate violation of professional ethics because these healthcare workers were inadvertently made the subjects of its study without taking any consent, and without telling them its potential side effects and listing the risk groups who should not take it, in its first recommendation. It cannot get rid of its responsibility by merely stating that you should do an ECG before taking it.
    In my view ICMR should be questioned for its seemingly criminal negligence by a court of law.

  6. The lancet paper is with complete with stats whereas ICMR issues statement that it is beneficial prophylactically. What is ICMR hiding? It is unbecoming of a top research body to issue statements without presenting facts

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