HCQ to Ivermectin: Why India has got it wrong in Covid-19 treatment

The very same day, India’s regulator, the Drugs Controller General of India (DCGI), green-lighted an emergency use authorisation for 2-deoxy-D-glucose (2-DG), a drug developed by the Defence Research Development Organisation (DRDO) in collaboration with Hyderabad-based pharma company Dr Reddy’s Laboratories.

The drug “helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence,” said a statement by the Ministry of Defence, adding that 2-DG will be of “immense benefit” to people suffering from Covid-19. The drug was then jointly launched on May 17 by Union Defence Minister Rajnath Singh and Union Health Minister Harsh Vardhan, who called the drug a potential game changer.

Two days later on May 19, however, the drug was left out of the revised national treatment protocol for Covid-19 that was released by the health ministry and prepared by experts at the All India Institute of Medical Sciences (AIIMS) and the Indian Council of Medical Research (ICMR). The guidelines are divided into three parts based on the severity of the Covid-19 disease. 2-DG also did not feature in the clinical management protocols updated by the health ministry on May 24. Samiran Panda, head of epidemiology and communicable diseases at ICMR, told Forbes India that experts are still studying data and evidence for the drug and that “regulatory approval is different from practice”.

By this time, however, there are several social media posts by patients requesting help to procure the drug as their doctors had prescribed it to them as part of their Covid-19 treatment. “Nobody knows why 2-DG was authorised,” says Dr Satyanarayana Mysore, HOD and consultant—pulmonology, lung transplant physician at Manipal Hospitals. “There are videos floating around on social media where the patient was administered 2-DG and recovered from Covid, which is an unbelievable claim and should be curbed.” Instead of this, he explains, what is needed is public scientific and peer-reviewed articles, or even preliminary studies, that provide evidence of the safety and efficacy of the drug.

Apart from 2-DG, the health ministry’s treatment protocol also does not feature Virafin, the drug developed by Ahmedabad-based Zydus Cadila that received an emergency use authorisation (EUA) from the regulator in April, apart from drugs like favipiravir and itolizumab that physicians across the country have been prescribing to patients, particularly in the wake of the raging second wave of the pandemic. In fact, antiviral drug Favipiravir, marketed by Mumbai-based Glenmark as Fabiflu, posted sales of Rs352 crore in April alone, “overtaking sales of drugs for lifestyle ailments such as diabetes, which have long dominated the market”, according to an article by Rupali Mukherjee in The Times of India on May 11.

A drug receives an EUA based on evidence from clinical trials and published data in peer-reviewed journals. Mysore agrees that approving drugs without sufficient clinical evidence leads to situations where these unproven drugs are sold by pharma companies, used by physicians, and sought out by desperate patients and their families.

Clinicians and experts have raised concerns around certain inclusions in the current treatment protocol too. “I have no idea on what basis they have still included hydroxychloroquine [HCQ] and ivermectin. There is absolutely no data behind it,” says Dr Jeenam Shah, consultant pulmonologist who practices with Wockhardt, Saifee and Bhatia Hospitals in Mumbai. HCQ, an anti-malarial drug, and ivermectin, an anti-parasitic drug, have been repurposed for Covid-19 treatment.

Both the US Food and Drug Administration [FDA] and the World Health Organization [WHO] recommend against using HCQ and ivermectin to prevent or treat Covid-19 infections, stating paucity of scientific evidence of their effectiveness and also a potential for side effects. The government, however, has been dispensing doses of HCQ. In Parliament in February this year, the health ministry stated that about 111.6 million pills had been distributed to states across the country till the end of January, and HCQ continues to be part of the guidelines.

The WHO has developed a living guideline on drugs to prevent Covid-19, where it states that the current use of drugs to prevent the coronavirus is “variable, reflecting large-scale uncertainty” and that numerous randomised trials for different drugs are underway to inform practice.

Health is a state subject in India, and while the Union health ministry issues treatment protocols, states form their own guidelines too. Experts Forbes India spoke with agree that the central and state governments have been unable to keep up with the rapidly evolving and changing science around Covid-19 treatments. Antiviral drug remdesivir, for instance, has been in huge demand during the second wave of the pandemic, and also finds its place in the updated treatment health ministry protocol under an EUA.

AIIMS chief Dr Randeep Guleria had said in an interview in April that remdesivir is not a “magic bullet and a drug that decreases mortality”. He added that India may use it since we do not have a very good antiviral drug, but remdesivir has a limited role and we should be very careful in its usage. Earlier, on November 20 last year, the WHO, in the wake of its Solidarity Trial, issued a conditional recommendation against the use of remdesivir in hospitalised patients, regardless of disease severity, as there was “currently no evidence that remdesivir improves survival and other outcomes in these patients”.

Many drugs have come into the market between the first wave and the second wave, like HCQ, favipiravir, and ivermectin, but there is no sufficient evidence to prove their benefits, says Dr R Narasimhan, pulmonologist at Apollo Hospitals Chennai, and chairman of the Respiratory Research Foundation of India. He adds the situation is also similar for antibodies like azithromycin and doxycycline, which found their way into central and state treatment protocols.

Convalescent plasma, another treatment that had found favour during the second wave, was dropped by the ICMR as a recommended mode of treatment in the May 17 revised protocol. Plasma had continued to find a place in the guidelines despite a trial by the ICMR last year on 400 patients last year finding no significant benefits from its use.

Registered doctors, however, are not bound by these guidelines and recommendations. The pressure and frustration to do something to improve the situation often pushes doctors to use unproven drugs that are either considered harmless or have shown results in some of their patients, says Dr US Vishal Rao, dean—centre for academic research, HCG Cancer Centre. He is also a member of the expert committee, Covid task force, Government of Karnataka.

“There is an eternal, colossal surge for evidence, but time is too short and the virus is running ahead of us. So it becomes hard for a clinician who is treating a patient to just stand by and say, ‘sorry, there’s nothing I can do’,” Rao explains. “None of these drugs, in the true light of science, have shown a reduction in deaths. But at this juncture, due to the sense of futility and frustration, clinicians are trying to be within the guidelines framework, but are open to use drugs where they see no harm and a potential benefit.”

Panda of ICMR agrees, saying that the guidelines clearly mention that evidence for drugs like HCQ and ivermectin is weak, and that physicians have to decide what is in the best interest of the patient on a case-by-case basis. “Once a physician becomes aware of the safety [of the medicine], he or she acts in the best interest of the patient. Now this does not mean that in the long run, in an evidence-based ambit, the same drug will find a place [in the treatment protocol],” he says.

Panda gives an example of how initially people thought that lopinavir / ritonavir, which are anti-HIV medicines, might help in Covid-19 treatment. “But in the Solidarity Trial, where ICMR was the lead organisation for India, the evidence showed that it was not useful. So there might be regulatory EUAs, but the drug will eventually fall out of favour if it does not stand the test of time and evidence,” he says, adding, “It’s not that we are taking a risk. This is how things progress in science and in public health.”

There are two ways of working with guidelines, says Dr Rahul Pandit, director--critical care at Fortis Hospital, Mumbai, and a member of Maharashtra’s Covid task force. One, just stick to what has been approved with evidence, and forget about everything else. Two, include drugs on the basis of compassionate or emergency use, and clearly mention whether there is strong or weak evidence to support it, and therefore whether the recommendation itself is strong, moderate or weak.

“Most guidelines are good levellers for treatment, but they acknowledge that nothing is sacrosanct. As long as there is good, scientific thought process and the intention of doing good, that is fine,” he says, adding that right now, only use of steroids and oxygen are backed by evidence, along with measures like lying in a prone position, ventilation etc.

According to Dr Pandit, drugs, when used, must be given at the right time, and for that, Covid care and symptom monitoring needs to be prioritised. “If you use drugs early, they either cause harm or don’t have benefits. If you use them late, certainly the benefit is gone, and whether it causes harm or not depends on what drug is used,” he says. Randomised trials suggest, for example, that tocilizumab may help only during a small time frame, within 24 hours of admission into the intensive care unit. “You can monitor timing only with constant care. There is an overdependence on drugs, but I would say that care—where you are able to detect subtle changes in physiology and treat the patient accordingly— should be the first priority.”

Dr Shah believes that the treatment protocol in its current form is confusing. He points out that “80 to 90 percent patients with Covid are going to recover irrespective, because they are mildly symptomatic and the disease process itself is such that second week onward, they start recovering,” he says. “Now the problem happens when a doctor prescribes XYZ medicines and believes that the patient has recovered because of the drug.” According to him, this is the reason for mismatched, incorrect or overmedication by doctors.

He says physicians need to be careful about the side effects of the drugs or the interactions between one medicine and another. For example, he explains, a combination of HCQ and azithromycin prolong the QT interval [of the heart’s electrical activity] and can subsequently cause arrhythmia. “Doxycycline and ivermectin can cause gastritis. Already patients with Covid might have some gastrointestinal problems, and if you give such drug combinations, the patient will feel further unwell. And that will not be because of the disease, but the medicine,” he says.

Narasimhan of Apollo Hospitals says that many a times, patients also actively seek prescriptions. “You tell a patient to just take paracetamol, monitor oxygen levels and get admitted only if the oxygen saturation drops below 90, he’s not happy. They want to get some medicine. So these drugs are also prescribed as a kind of trade-off between patient and physician,” he says.

Dr Shah agrees. “I have faced so much resistance with my own patients,” he says. “They request prescriptions for tocilizumab and other drugs, despite being told there is no evidence to prove that it works or that it might lead to complications. They have heard that their friends or relatives got better with a drug, and they want it too.”

Dr Mysore of Manipal Hospitals believes one positive development in this scenario is use of monoclonal antibodies, which he says will bring down the extent of infection and prevent hospitalisation. Recently, pharma companies Roche India and Cipla announced that their first batch of antibody cocktail (casirivimab and imdevimab), which has received an EUA from the regulator, will be available for treatment of high risk Covid-19 patients. It is priced at Rs59,750. Zydus Cadila has also approached the DCGI for permission to undertake phase 1/3 clinical trials of a monoclonal antibodies cocktail that can neutralise Covid-19 infection. It claims to be the only Indian company to have developed a neutralising monoclonal antibody-based cocktail for treatment of Covid-19.

As far as drugs like HCQ and ivermectin are concerned, they need to be taken out of the treatment protocol, Dr Mysore says, and authorities must be transparent about strong clinical evidence. “Unfortunately, there are silos and red tape issues. Drugs are being authorised left, right and centre under the banner of emergency use,” he says. “I feel even if you give an EUA to a drug, you are bound to follow up on the data, track for side effects or adverse events, keep a registry and have a broad-based consultative network that guides follow-ups on approved drugs at various levels and makes that data available.”

He calls for an all-India committee with government, private players and central institutes when it comes to finalising treatment protocols. He says, “It’s been a journey of 1.5 years, where drugs that were once made heroes have now become villains on the block. You need to rationalise the protocol and revise the guidelines.”