As COVID cases surge, has vaccine overshadowed crucial antiviral drug?

Countries are racing against each other and time to develop vaccines that prevent COVID-19, but with a second wave likely to hit India like the West and the sick returning to hospitals, have we overlooked the crucial antiviral drugs?

Remdesivir was once championed by scientists across the globe. But when the antiviral drug, originally designed to treat both hepatitis and a common respiratory virus proved useless against those diseases, it was consigned to the pharmaceutical scrap heap. One virologist, however, continued his research on it. Professor of Paediatrics and Microbiology at the Vanderbilt University Medical Centre in Tennessee, United States, Mark Denison began hunting for a drug to treat COVID-19 almost a decade before the contagion hit the world in December 2019. Denison is an expert on the deadly Coronavirus family, members of which previously caused the SARS-CoV-1 outbreak in 2002 and the MERS-CoV (Middle East Respiratory Syndrome Coronavirus) epidemic in 2012. He was certain that the viral group would emerge soon, this time, with deadlier consequences. So, he got to work in 2013. Four years later, he found that remdesivir could shut down the replicating machinery of several Coronavirus variants. 

When an alarm was raised about SARS-CoV-2 (the virus that causes COVID-19) in January last year, Denison already had a potential treatment.

One vial of the drug remdesivir seen at a press conference about the start of a study with the drug amidst the COVID-19 pandemic last year. Pic/AFP

Remdesivir became the first drug approved by the Food and Drug Administration (FDA) for treating patients infected with COVID-19. It was made available to patients for compassionate use that same month. In late June, Cipla launched remdesivir in India under the brand name Cipremi [costing just above $50 per 100 mg vial], along with subsequent launches by other pharmaceutical companies. By September last year, Cipla had sold more than 3,00,000 vials of the drug across the country. Even Mumbai-based BDR Pharmaceuticals sought the Drug Controller General of India (DCGI)’s approval to manufacture and sell the generic version of remdesivir.

Yogendra Kumar Gupta of AIIMS, who specialises in clinical pharmacology, wrote in the Indian Journal of Pharmacology in August 2020: “In India, despite all the proactive measures by the central and state governments such as lockdown and social distancing, the COVID-19 positive cases have continued to increase. Hence, with recent positive development with remdesivir, we need to be ready with measures to make sure the availability of the drug to a huge population at an affordable price.”
Dharmesh Shah, chairman, BDR Pharmaceuticals, says, “Remdesivir, for sure, worked for patients with lung infection and helped immensely in speedy recovery, whereas another antiviral called favipiravir, also launched by BDR, worked for speedy recovery of mild and asymptomatic/moderate patients. Originally invented in Japan for influenza in 1998, and later during COVID-19, favipiravir was launched by BDR in India under the brand name BDFAVI. Scientists observed that favipiravir works by inhibiting the replication of viral germs within infected cells, thereby mitigating the virus ability to spread from one cell to another.”

Dr Basavraj Kuntoji

BDR developed favipiravir in 200 mg strength, with a strip of 10 tablets. But with a long wait for the vaccine, the demand for both remdesivir and favipiravir started rising in India. It was said that their therapies were improving the care of COVID-19 patients, putting doctors in a better position than they were when the virus surged last January. Somehow, though, efforts to increase production of these drugs or even discover new ones have not had much success. The world leaders are clear in their single minded focus—to find a life-saving vaccine.
 
Nearly a year into the pandemic, as patients continue to die across the world, and widespread vaccination is still months away, doctors need these precious few drugs to fight the virus. India might be even staring at a second wave. Dr Basavaraj Kuntoji, consultant, internal medicine, Manipal Hospitals, Bengaluru, says, “The COVID-19 cases in India have crossed 1.1 crore with a total death toll of 1,56,500. September last year was the worst hit month when the daily patient count reached close to one lakh. However, the cases began to dip, indicating that the situation is under control. The average number of daily cases reduced to 10,000 during the first fortnight of February 2021. However, there has been a sudden surge since the third week of February, with 14,199 COVID-19 cases in that week alone. The number of daily deaths has also started rising with a total tally of 100 deaths on February 23.”

Iqbal Singh Chahal, who was appointed as the new Brihanmumbai Municipal Corporation (BMC) commissioner during the pandemic, visited Nair Hospital in Mumbai in May last year. File photo

According to Dr Kuntoji, India has not achieved herd immunity yet, which requires infection in at least 75 per cent of the population. “Currently, only 22 per cent of the Indian population has been exposed to the COVID-19 infection. The second wave may be due to the modified behaviour of the pathogen, which is very common with viral infections,” he says.

The human factor may also have played a major role in causing the second wave. “Most people are not wearing a mask, maintaining social distancing, and frequently sanitising their hands. Further, the markets are opening with full strength, and the public gatherings were allowed until recently without any limitations. If a similar trend of rise in cases continues, there is an immediate danger of entering into the second wave of the pandemic, which may be worse than the first. We may have to go into complete lockdown and impose extensive travel bans. Hospitals may be flooded with COVID-19 patients with severe complications,” he warns.
Dr Dinesh Dhodi, head of pharmacology department, Grant Medical College and JJ Hospital, says, “People who were never exposed to the virus and stayed indoors through all lockdowns have now started to step out. Naturally, this vulnerable lot is coming in contact with potential infectors, thus increasing transmission.”

Dr Dinesh Dhodi, Dharmesh Shah and  Dr Ayesha Sunavala

So, why then are we not prioritising the manufacture of antiviral drugs to keep going until the entire population is vaccinated? The situation is more or less the same in America, the worst-hit country in the world. The US government has pumped $18.5 billion into vaccines. But its investment in drugs is far smaller, at about $8.2 billion. Studies to find newer drugs were poorly organised, too.

In their defense, Dr Kuntoji believes that Indian pharma firms are not concentrating on developing the COVID-19 vaccine alone. “We should understand that drug development is a complex, costly, and time-consuming process. It becomes even more difficult when the development is for a disease with limited information [available on it]. Researchers believe that COVID-19 will exist in society forever. However, the severity of illness will not be high. Having said that, as the complications during and after the COVID-19 infection are high, there is indeed a need for life-saving drugs that treat the infection before it causes severe damage to multiple organs,” he explains.

Dr Kuntoji thinks that the pandemic hit various export and import businesses throughout the world, due to lockdowns and restriction on international commercial channels. This also resulted in the reduced production of drugs. “There is an increased risk of global shortage of COVID-19 drugs because we have several infected populations. Governments are developing policies to prevent the shortage. The Center for Infectious Disease Research and Policy (CIDRAP) reports that out of 40 critical medicines in the United States for COVID-19, 72.5 per cent (29) are experiencing shortage. [This means that] healthcare professionals either look for a substitute or may allow the patients to go without treatment in the absence of critical drugs,” he informs.
 
Explaining the difference between an antiviral drug and vaccine, Dr Dhodi says that vaccines prevent or mitigate infections. “When vaccinated, the immune system of the body produces a specific response that fights off the infection when exposure to the virus occurs at a later stage. Antivirals, on the other hand, are drugs that can treat people who have already been infected by a virus. They also can be used to prevent or limit infection when given before or shortly after exposure, before illness occurs. But chances of doctors prescribing an antiviral to a person before he or she is even exposed to the infection are very less.”
Dr Dhodi, who is also the co-investigator in the Bharat Biotech’s Covaxin trial at JJ Hospital, says that Mumbai hospital ICUs are not overwhelmed right now despite the surge in cases, but if caseload increases, we may have to think of producing more antivirals.

Evidence gathered so far suggests that antivirals are useful only if used early in the disease state. Early treatment versus late-stage treatment with antivirals in those with moderate to severe disease has been significantly associated with reduced mortality rates. “However, one of the key challenges in COVID-19 appears to be the time lapse between the infection onset and the start of the treatment. Most patients seek treatment about seven days after symptoms come on, and thus receive the first antiviral treatment only after reaching the hospital. This results in reduced efficacy of the antiviral drugs,” Dr Kuntoji explains. 

India being the ‘pharmacy of the world’ has helped the country so far. He adds, “India has over 10,000 medicine manufacturing units. Our country contributes about 20 per cent of the total global exports of generic drugs. During the initial phase of the pandemic, the Health Ministry had advised the All-India Organization of Chemists and Druggists (AIOCD) to ensure the availability of critical drug used for managing COVID-19 symptoms. There are no reports of the shortage of medicines in India. Moreover, India is helping other countries by supplying them with both drugs and vaccines. The Indian pharmaceutical market has seen a surge in the sale of COVID-19 drugs. The sale of remdesivir was at R510 crore, while favipiravir sale was at R471 crore this January.”

Shah agrees, and says that priority developments for life-saving drugs are running parallel as planned in India. “The pandemic was never envisaged by the scientific world and hence, the inoculation drive is a must to win the confidence of people. That doesn’t mean the country has failed to prioritise production of drugs. Both vaccine and drugs are equally important in today’s scenario.”
 
India started the world’s largest inoculation drive in January this year, inducing hope among many. But the fact remains that it forgot to set up an organised network of hospitals to carry out large drug trials and quickly share the data. Dr Ayesha Jamshed Sunavala, consultant, infectious diseases, PD Hinduja Hospital & MRC, thinks, “There’s still a lot of research on, if not on curative antivirals, then another sort of medication to treat the immune problems that one has with COVID-19, and the inflammation that one develops with severe COVID. So I think there has been an equal amount of work going on in drug development. Of course, vaccines certainly seem to overshadow the picture now. The focus had shifted from finding curative antivirals because time and again we found that most antivirals have failed in the past. I don’t think there’s any question of which group works better.”

The efficacy of remdesivir was questioned by the WHO. In fact, in November last year, the WHO recommended against its use for treatment of COVID-19. “The antiviral drug remdesivir is not suggested for patients admitted to hospital with COVID-19, regardless of how severely ill they are, because there is currently no evidence that it improves survival or the need for ventilation,” it said in a statement.

So, what support do we have now before everyone is vaccinated? At present, paracetamol is being used for symptomatic treatment of fever and pain, oxygen therapy for low blood spO2 and antitussives for cough. Dr Sunavala says, “The most important thing we have is steroid and oxygen care support. Details of the recovery trail tell us there is tocilizumab, which has showed improvements when used at the right time on a select population. We have remdesivir, but we do not have much data backing it.”

Widespread vaccination, therefore, is the only way forward, she adds, saying, “Because patients don’t require treatment. Most patients with mild/moderate COVID-19 require observation or close medical attention and perhaps a little oxygen support. But to prevent the healthcare system from getting overwhelmed with the severe cases of COVID-19, the only way forward is vaccination. Of course, 100 per cent universal vaccination will take a very long time, but the faster we get through it, the sooner we will come out of it.”

But in the race for vaccine development, we are forgetting what has happened before when the the world tried to rush a vaccine. “History tells us that speed kills,” says Arthur Caplan, a bioethicist at NYU Langone Medical Center and co-author of an article in the Journal of the American Medical Association. The key lesson about the hazards of rushing a vaccine into production comes to us from Berkeley, where a pharmaceutical company called Cutter Laboratories was chosen in 1955 by the then government as one of five private manufacturers of the Salk polio vaccine. Because of a series of manufacturing errors and government oversight, however, some of Cutter’s vaccine lots were contaminated with the live virus. An estimated 40,000 children contracted polio from Cutter’s vaccine. Many family members who had not been inoculated contracted the virus from their vaccinated children. About 200 victims were permanently paralysed, and 10 died.

Should our priorities be corrected then? Dr Kuntoji doesn’t think so, “Vaccines generally take between eight and 10 years in development, while drugs take approximately 12 years for completing the trials. The fastest approval process for the vaccine, before the COVID-19 vaccine, was for the mumps vaccine in the 1960s, which took around four years. COVID-19 had put tremendous pressure on the global healthcare system. The resources were insufficient to provide medical facilities to all the patients. Thus, it was imperative to prevent the development of infection through vaccination. Another apprehension, while developing a drug, might be its efficacy on all the COVID-19 patients. Having said that, pharmaceutical companies are simultaneously researching both vaccines and drugs. Fortunately, the early results of the clinical trials on vaccine were excellent, thereby motivating the companies to direct their resources for vaccine development.”

But he agrees that drugs may be able to keep some patients out of the hospital and, severe hospitalised patients out of ICUs. “They can serve as a bridge to survival as other researchers hurry to develop the real virus slayer—a vaccine,” Dr Kuntoji concludes.

$18.5b v/s $8.2b
The US government’s investment in COVID vaccine development in comparison to drugs development

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