It’s puzzling why medications already in the market are not being put through essentially accelerated phase IV clinical trials, especially those that had value against SARS, particularly in China and Italy.
The chaotic scenes at major international airports including Dulles International Airport in Washington, DC and Indira Gandhi International Airport in New Delhi exemplify the catastrophe that has befallen the entire world. Never before in recent memory has a pandemic so devastated national economies, and the very fabric of society, with grey eminences’ unseemly fights over toilet paper in suburban malls, assuming that they would need to prepare for quarantine, being broadcast worldwide by the Twitterati.
Covid-19, or novel Coronavirus Disease 2019, has struck at the heart of normal life everywhere, with even the Tokyo Olympics at risk of being postponed, as competitive countries’ athletes are unable to train amidst mass lockdowns.
There is little doubt that the disease originated in Wuhan, China, and during the early months, 99% of the infected cases were concentrated in China. Later, given the extensive air travel links in a rising economy that China has been, the disease started to transmit to other countries. Virtually, every case in India has had foreign origins, with the first few cases having been Keralite medical students who had been studying in Wuhan. That is why the Indian government’s multi-ministry task force headed by Health and Science and Technology Minister Dr. Harsh Vardhan virtually ended all inbound air and other travel from other countries. Testing, which currently requires a polymerase chain reaction (PCR), takes time and expertise to perform, and has contributed to some of the chaos we see at airports as suspects are tested using samples from their upper respiratory system.
Having organised a conference on Emerging Infectious Diseases in 1998 with Nobel Prize winner Prof Joshua Lederberg, whose theories (along with his scientist wife Prof Esther Lederberg) explain even today the phenomena of viruses that use bats as a reservoir and that can then mutate and jump to humans to start transmitting human-to-human. 20% of all mammals are bats (humans too are mammals), thus bats are very numerous, seen on every continent and live near humans and livestock, and bats are the only mammals capable of powered flight.
Three other zoonotic coronaviruses have been identified as the cause of large-scale disease outbreaks—Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Swine Acute Diarrhoea Syndrome (SADS). SARS and MERS emerged in 2003 and 2012, respectively, and caused worldwide pandemics that claimed thousands of human lives, while SADS struck the swine industry in 2017. Covid-19 is closely related, structurally, to the SARS coronavirus, hence scientifically, the terminology SARS-CoV-2 (for Covid-19) and SARS-Cov-1 (for year 2003 SARS) are being used. Coronaviruses are named for the crown-like spikes on their surface; corona means crown in Latin, derived from Ancient Greek. A scientific paper published by academics from the Chinese Academy of Sciences’ Wuhan Institute of Virology in 2019 in the international journal Viruses pointed to over two dozen coronaviruses that use bats and others that use birds as reservoirs. Hence, there is future potential for more zoonotic coronaviruses to mutate, jump to humans and start transmitting between humans.
Pandemonium, whole populations switching to surgical mask attire, mass quarantines, trillions of dollars in lost GDP worldwide, entire industries like the airline and travel industry facing bankruptcy with concurrent millions of layoffs, characterise the current COVID era. And all because of the assumption in society that Covid-19 carries with it a death sentence for an unfortunate minority who are severely affected, who get viral pneumonia along with their often concurrent co-morbidities like hypertension and diabetes, and the damaged lungs of chronic smokers. At this time, it still appears that only around 2% of the infected go into severe respiratory distress and death. A key differentiator between the severely affected and the rest is the development of viral pneumonia. Many of the remaining only suffer symptoms that appear to be a bad flu, fever, cough and rhinitis. Thus there is also the issue of medical confounding, with many cases of flu being mistaken for Covid-19, with concurrent alarm until the PCR-based test is done.
As in every pandemic, where the organism came from is interesting and always controversial, but more important is monitoring and dealing with where it is going, especially in the coming years(s). Covid-19 is caused by a highly infectious new coronavirus that is moving from human to human, and is spread by droplets sprayed from coughs and transmitted between handshakes and from recently touched surfaces such as doorknobs. Hence, the desire by health authorities and indeed internal security apparatus to confine everyone who has had any contact with an infected person into quarantine/isolation.
A realistic strategy is needed to deal with the problem of emerging infections, of which Covid-19 is the latest illustrious class member, that include SARS, the West Nile encephalitis virus, Hantavirus, Influenza viruses, Ebola hemorrhagic fever virus, and HIV—the AIDS virus. These new and often relentlessly mutating viruses are produced from the epidemiological brew that facilitates viral promiscuity wherein genetic material is exchanged between micro-organisms in bats, birds, cows, pigs and other animals that are reared or live in close proximity to humans in some parts of the world. From time to time, these viruses of animal origin are able to propagate into and by humans. This should not be surprising in view of Nobel Prize winner Joshua Lederberg’s finding that 400 to 500 retroviruses are firmly integrated into the human genome, something that would be shocking to racial purists. So much more would need to be researched by every country’s research establishment, with or without international collaborations.
HIV/AIDS too was once considered a death sentence. Then came anti-retrovirals (ARVs) that converted the scary disease into just another disease requiring life-long chemotherapy. Indeed, Indian pharma has much to be proud of for reverse-engineering ARVs and offering them at a fraction of their then price of $10,000 per year, instead at $1 per day or $365 per year that was a game-changer. ARVs have since become even lower in cost, and are generally provided free to all AIDS patients, worldwide. I remember participating as an expert in a year 2001 trip with senior officers of a major New York foundation that was subjected to a tongue-lashing by Dr Yusuf Hamied, chairman of CIPLA, and his officers, for the sluggish speed at which the world was deploying ARVs that had proven value against HIV and had been made affordable by Indian pharma. The issue of patent rights etc, go away after 20 years in any case, and today, ARVs such as lopinavir and ritonavir that have had proven effectiveness in SARS now nearly 20 years ago, are being tested against Covid-19. This issue was also raised in the Rajya Sabha last week by Dr Manas Bhuiyan and Minister Dr Harsh Vardhan replied that the government, especially ICMR, was seized of the issue and was keenly looking into applying ARVs and even chloroquine against Covid-19 and drawing on global knowledge in this respect. While anecdotal evidence does point to treatment value, a randomized, controlled, open-label trial of 199 adult patients with severe disease done by Chinese academics and published on 18th March 2020 in the New England Journal of Medicine, among the most prestigious medical journals worldwide, did not show any significant time to clinical improvement difference of the lopinavir-ritonavir group over the other 100 receiving standard care. A modified intention-to-treat analysis did reveal clinical improvement shorter by 1 day over standard care. Larger studies of those with severe illness would be needed. And perhaps the clinical value could just be for those with mild disease, blocking progress to severe disease which would require yet another type of clinical trial. Other drugs include the Japanese flu medicine favipiravir, also known as Avigan, an antiviral drug being developed by Toyama Chemical (Fujifilm group) with activity against many RNA viruses. Similarly, remdesivir is a novel antiviral drug in the class of nucleotide analogs, developed by Gilead Sciences, and is being studied against SARS-CoV-2 infections. Once there is a cocktail of medications with proven value against Covid-19, the death sentence image disappears, and the world can largely go back to normal. So it is puzzling why medications already in the market are not put through essentially accelerated phase IV clinical trials, especially those that had value against SARS, particularly in China and Italy that have had the bulk of the infections and deadly serious Covid-19 cases.
Instead, as usual, there is a rush in international circles to fund vaccines R&D, which are great if they can be developed in time to make a real difference. It brought back many memories of the hundreds of millions of US dollars squandered in the 1990s and early 2000s into quixotic ventures to create an AIDS vaccine that were funded by billionaire-philanthropists with no background in biology or medicine, who simply ignored the pleas of many experts who had the temerity to point out that making a vaccine against HIV, that is a highly mutating organism, is nearly impossible. The crude analogy to a vaccine is a sniper’s rifle as compared to ARVs being akin to machine guns. Many doctors in clinical practice work with the medical equivalent of machine guns that can fire off multiple bullets, one of which is bound to destroy the invading organism.
Proper public health and medical surveillance, especially backed up by digital means and high science, will ensure that rapid and firm actions can effectively counteract the greatest threats posed by dangerous diseases. Newly mutating viruses will continue to emerge, as they always have, but a well-prepared world into the future will ensure that the catastrophes associated with Covid-19 will just become a bad, distant memory.
Dr Sunil Chacko holds degrees in medicine (Kerala), public health (Harvard) and an MBA (Columbia). He served in the Executive Office of the World Bank Group, and has been a faculty member in the US, Canada, Japan and India.