The Search

WHEN A 59-YEAR-OLD lecturer in Aurangabad came to know she had tested positive for Covid-19, her first thoughts turned to her family and students. She had returned from a holiday in Russia via Kazakhstan, the two places she is suspected of having picked up the infection, over 10 days earlier, and had mingled freely with others, including even taking classes for her students.

“When I was isolated in the hospital, I was constantly praying, ‘Oh god, nothing should happen to [my family and students]’,” she says, requesting she not be identified by name.

Apart from her family members who were put under quarantine, around 20 students who had come in contact with her and begun to display flu-like symptoms were also quarantined. Since she was the first confirmed case of infection in Aurangabad, the city went into panic. Within a day’s time, a photograph of her and her husband, taken from their Facebook accounts, claiming they had died was doing the rounds on WhatsApp. “It was just a very bad time for us,” her son says, recounting the ordeal.
The lecturer had been feeling ill for a few days before she had got admitted, popping antibiotics to keep a slight fever and shivers down. In a few days, she began feeling breathless too. “[At the hospital] the drugs they gave me were very strong and I would be very exhausted,” she says.

And then she recovered.

Just four days after she had first tested positive, two tests conducted 24 hours apart found her free of infection. By the ninth day, she was home. None of her students or her family members were found infected either.

“It’s something even we [doctors in the hospital] are discussing—how she recovered so quickly,” says Dr Himanshu Gupta, the doctor who treated her in Aurangabad’s Dhoot Hospital. There were many things, according to Dr Gupta, that worked in her favour, from her underlying good health to an early diagnosis. “All this means we could start ART [anti-retroviral therapy] quite early. Unlike other cases, where patients are diagnosed late and the infection has progressed to a severe form,” he says.

Anti-retroviral therapy—or as it is in this case, a fixed dose combination of lopinavir/ritonavir that is sold under the brand name of Kaletra and used to treat HIV patients—is one of several drugs that was originally designed for some other ailment but is now being repurposed to fight the COVID-19 pandemic. We don’t know how well it works, or which among them is better or even if it really works. A few anecdotal accounts from doctors and non-peer reviewed studies with small sample sizes seem to suggest that some of them are working.

The traditional way of developing drugs for new infections takes years. But this new strain of the coronavirus isn’t giving us that leisure. In the middle of a full-blown pandemic, when there is no time to invent new drugs or conduct comprehensive foolproof studies, a vaccine still a year or more away and vast swathes of the world currently in lockdown, a race is underway in labs across the world to rediscover old and approved drugs that can be repurposed for this infection. Until the end of last month, according to an article in the Economist, China’s Clinical Trial Registry has listed 105 trials of drugs and vaccines intended to combat this pandemic. By March 11th, the National Library of Medicine, its American equivalent, had listed 84. Very few patients among those infected will progress to severe forms of the disease, but at a time where healthcare services are coming under a huge strain, the purpose will be served if any of these drugs even shortens the duration of recovery time.

From anti-HIV to anti-malarial medicines, several old drugs are being repurposed to fight the virus. We don’t know how well they work, or which among them is better or even if they really work

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Dr Om Shrivastav, a top infectious disease expert in Mumbai who is currently treating some of the patients suffering from COVID-19, points out that, apart from anti-HIV drugs, some other drugs such as those traditionally found to be working against H1N1 (swine flu), such as oseltamivir, also seem to show encouraging results in India. “So it’s a combination of a number of these drugs that have shown some encouraging results. But that is still not mainline, because you will need any of these to go through scientific scrutiny. It’s encouraging, but it is still early,” he says. “We are in a state where there is going to be evidence that may appear good today but fall by the wayside tomorrow. So it’s a work-in-process. You have to remember that this is a brand new virus. We only know it for the last three or three-and-a-half months. It’s not enough time to say we know everything about it.”

This virus, various studies show, essentially looks like a ball with spikes. Our first point of infection is when these spikes stick to a protein which is found on the surface of our cells called ACE2. It enters our cells using its proteins—and since viruses cannot reproduce on their own—they effectively turn our bodies against ourselves, hijacking our cells making it produce more and more of these viruses.

Scientists are currently trying to use the roster of pre-existing drugs to do one of two things. They are looking at drugs that can attack the virus’ own proteins and prevent it from doing things like entering human cells and making our cells into coronavirus factories. Or they are trying to find which proteins in our cells are required by the virus to infect and multiply and then find drugs that are already available which might stop such an interaction from taking place. According to Nevan Krogan, a researcher from the University of California, San Francisco, writing on the portal The Conversation, they have managed to find 332 human proteins that the coronavirus co-opts, and so far they have found around 69 drugs (27 FDA-approved and 42 in clinical or pre-clinical trials) that seem to interact with 66 of those proteins.

I DON’T WANT TO make a single rupee on this,” says Omkar Herlekar, the chairman of the Mumbai-based company Lasa Supergenerics, which is working towards manufacturing favipiravir, an old anti-viral drug that some studies show is effective in the treatment of patients suffering from a COVID-19 infection. “I don’t even mind if I have to put Rs 20 crore from my own pocket—and I find that the infection doesn’t take off and there is no mass outbreak [in India].”

Herlekar is a colourful figure, whose company otherwise manufactures raw ingredients required in the production of drugs. He had been following the news of this new strain of coronavirus ever since it first broke out in Wuhan and the various studies that show which of the old drugs hold promise against it. “Once this outbreak was prominent, we thought of doing research on which [old] drug might work. Then we came to know favipiravir is a drug of interest. So we thought, why not conduct trials? What’s worse that can happen?”

Favipiravir is an old drug, originally owned by the Japanese company Toyama Chemical and now off-patent, which is used to treat influenza. Listed by the World Health Organization as part of its experimental protocol for treating the disease, recent clinical trials in Wuhan and Shenzhen in China involving 340 patients, according to The Guardian, show that those given the medicine recover more quickly than others (they turned negative for the virus after a median of four days after becoming positive, compared with a median of 11 days for those who didn’t get the drug). There are, however, suggestions that the drug isn’t as effective in people with more severe symptoms.

“There are many old drugs like this which haven’t been looked into for decades, which are not taken seriously anymore. But then an epidemic happens and there’s panic and a forgotten drug shows promise,” Herlekar says.

Herlekar’s Lasa Supergenerics is currently working on an incredibly strained timeline. He has already applied to the Drug Controller General of India for a licence of this product (he expects permissions to come through within a day or two), while he is simultaneously developing the drug along with the Mumbai-based Institute of Chemical Technology. “Time is of the essence now,” he says, and if it all goes according to plan, he plans to have the drugs ready for use in between four and six weeks. “You won’t find one gramme of this drug right now [in India]. So mine will be the first one out.”

Lasa Supergenerics isn’t the only manufacturer interested in the drug. The Indian pharma giant, Cipla, is working—along with CSIR-IICT in Hyderabad—to manufacture favipiravir, along with two other drugs, remidesivir and bolaxavir.

IICT director S Chandrasekhar and Cipla representatives did not respond to queries for an interview, but in a press conference a few days ago, Chandrasekhar said: “Favipiravir and remidesivir have already undergone clinical trials and, hence, we will not require much time to make them as the raw materials are readily available. It could take about six to 10 weeks to make them. Process to start bolaxavir molecule will begin now.”

Scientists are using old drugs that can either prevent the virus from making our cells into coronavirus factories or stop it from using the proteins in our cells

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Remdesivir, originally developed by the American biotechnology firm Gilead Sciences for use against Ebola fever, is currently one of the most talked-about drugs in dealing with the current pandemic. It was never, ultimately, used for Ebola fever, but lab tests have shown it works against a range of other RNA-based viruses, including the SARS coronavirus of 2003. According to early lab tests, it appears that it can block the replication of this current coronavirus too. There are various trials studying remdesivir’s efficacy in COVID-19 patients underway, including two in Asia that will altogether involve around 1,000 infected people, whose results will probably show up sometime in late April.

Cipla also produces a range of other medicines either currently being used or in consideration for use against the virus, from the anti-HIV drug combination lopinavir/ritonavir, the antiviral oseltamivir, the antibiotic azithromycin to the other much talked-about anti-malarial drug hydroxychloroquine.

Even if any of these drugs prove to be highly effective, in the event of a largescale outbreak, the issue will be whether drug production can be quickly scaled up. “My problem is, suppose coronavirus gets out of hand, how do we cope? I can only make a particular amount. I can’t make for a million patients. But 5,000-10,000 patients we can cope,” Cipla’s Chairman YK Hamied told The Hindu Business Line.

One much-anticipated drug, both very familiar in India and produced quite widely, is the anti-malarial drug hydroxychloroquine. Donald Trump has called it a “gamechanger”, and although some small studies have suggested it is quite effective, larger studies are still required. “Anecdotal reports may be true, but they are anecdotal,” Anthony Fauci, an immunologist who is a member of the Coronavirus Task Force set up by Trump and who routinely addresses the media, said recently. Another such drug is camostat mesylate, meant for pancreatic inflammation.

In India, some doctors report to have been able to treat COVID-19 patients with anti-HIV drugs. These include, apart from the Aurangabad patient, cases in Kerala and Rajasthan. However, according to a recent study in the New England Journal of Medicine, the lopinavir/ritonavir combination didn’t deliver any observed benefits above the standard care protocol in a randomised controlled trial of 199 COVID-19-infected patients.

One doctor currently treating some COVID-19 patients in India who is using the anti-malaria drug hydroxychloroquine along with the antiviral oseltamivir, usually used against H1N1, claims it is currently very difficult to say, because of the absence of rigorous scientific studies, which of the drug is better than the other. “Right now, there is evidence of the use of chloroquine. But [which drug is to be used by doctors in India] is meant to be recommended on an individual perception of what might work,” he says.

The Aurangabad patient, now recovering at home, does not dwell much on the drugs she was given. “I think God was very kind to me,” she says.

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Lhendup G Bhutia

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