Virus World

Background

Methods

Findings

Interpretation

The last time the world needed an antiviral medicine as quickly as possible, Daria Hazuda, vice president of infectious disease and vaccine discovery research at Merck, answered the call. Around 150,000 Americans were infected with HIV each year when rates peaked in the mid-1980s, and by the year 2000 nearly 500,000 people had died of AIDS in the U.S. Hazuda’s research at the time focused on HIV’s ability to insert its genetic material into the the human genome. Her lab developed a novel way to target that process with a drug called raltegravir, which was approved for use in 2007 and is still used today.  Now, she hopes to develop a drug for COVID-19 — at a substantially faster pace.  While most of the world’s attention is currently laser focused on getting vaccines to more people to stem the spread of the coronavirus, there’s also significant pressure on scientists to find a cure.  Doctors have some medications they can use to treat the effects of COVID-19, but developing a drug that targets the virus itself is a complex and costly procedure. More than a year into the pandemic only one antiviral treatment — remdesivir — is currently recommended for use in the U.S., and experts say it is not nearly effective enough. “Vaccine manufacturers are making next generation vaccines to try and stay one step ahead, but it is unpredictable. So you need other interventions to address the potential evolution of the virus,” Hazuda said. She and her team, along with researchers at Miami-based Ridgeback Biotherapeutics, worked seven days a week in the spring of 2020 to find a possible treatment for COVID-19 and prepare for the clinical trials necessary to prove its safety and effectiveness. Their drug, molnupiravir, is one of two powerful medicines to treat COVID-19 that are nearing the end of clinical testing.  “The day started really early and ended really late at night,” Hazuda said. “But there was a tremendous sense of mission. Everybody wanted to help even though they were exhausted. There was so much we all had to do.” Scientists are hopeful that new drugs designed to stop the virus’ deadly reproduction could reduce hospitalizations and deaths from COVID-19. The drugs offer hope and a contingency plan for unvaccinated individuals, particularly in low-income countries lagging far behind in the race to vaccinate. 

Chasing a moving target

Viruses mutate constantly, making it challenging to find a medicine that will not just work, but continue to work as the virus morphs. Mutations can change the shape of viruses’ proteins and thereby make them resistant to drugs. The hunt for effective antivirals is largely a hunt for a “conserved target,” such as a protein that rarely changes its shape even as the virus mutates.  Since scientists shared the sequenced genome of the novel coronavirus in January 2020 — detailing the specific genetic information and proteins of the virus — researchers have worked at breakneck speed to find a targeted medicine. Hazuda’s experience with HIV and Hepatitis C helped her team quickly rule out targets in the SARS-CoV-2 structure that were likely to change as the virus mutated and focus instead on “very highly conserved targets to minimize the potential of developing resistance,” she said.  Antiviral medications often target a virus during the process of replication, when it uses our cells’ resources to make copies of itself — leading to cell damage and the release of more virus. By early March of last year, Hazuda had narrowed her search to compounds aimed at proteins that could copy the virus’s genetic material. Her team came across a pre-clinical publication from an Emory University scientist on molnupiravir, a compound initially developed for influenza and other viruses. Research suggested the compound could make it harder for the virus to replicate itself by interrupting the RNA polymerase enzyme, which acts like a copy machine for the viral genome. In various academic labs, molnupiravir has demonstrated activity against flu and many different types of coronavirus, including MERS and the common cold.  “We were very interested in finding an agent that would have the potential to be not only active against CoV-2, but potential future outbreaks or pandemics caused by other coronaviruses,” Hazuda said. Because Ridgeback Biotherapeutics had the rights to molnupiravir, Merck began collaborating with the smaller pharmaceutical company to test the safety of the compound and prepare it for clinical studies.  The idea is that molnupiravir could be taken as an oral pill by symptomatic patients who test positive for COVID-19, before their illness is severe enough to require going to a hospital. The hope is that it can stop the virus in its tracks, before it can replicate uncontrollably and cause a person to become more sick. One phase 2 clinical study showed that molnupiravir is unlikely to significantly change the illness of those people who are hospitalized with COVID-19, but Hazuda is hopeful that phase 3 trials — expected to conclude by the end of the year — will demonstrate its effectiveness as a treatment that can be used outside of the hospital for people with mild to moderate cases.

Adolfo Garcia-Sastre, the director of the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai, also spent the spring of 2020 looking for a medication that could thwart the coronavirus’ lifecycle, but at a different stage. He sought a drug that influences the human proteins that the virus uses to build its components.  Because viruses hijack human cells and use their proteins (called factors) and other materials for their own purpose, identifying the factors they rely on can be a first step toward halting their actions.  Garcia-Sastre’s collaborators at the Quantitative Biosciences Institute at the University of California, San Francisco, identified more than 300 human factors most likely to make an impact on viral replication. Then, his lab tested around 90 drugs that are known to affect these factors. They landed on plitidepsin, an injectable medicine developed by Spain’s PharmaMar and used in patients with multiple myeloma, a type of blood cancer. It was shown to interfere with the function of a human factor called eEF1A, which the virus uses in the assembly of  its proteins. So far, plitidepsin seems to overcome some of the difficulties in finding a drug that targets virus replication. One is that often their effectiveness in the lab or in animal testing doesn’t carry over to humans. Another is toxicity: The concentrations required can cause undesired effects in human cells. Plitidepsin passed the critical phase 1 clinical trial conducted in Spain, showing that toxicity is not a barrier to use. The ongoing phase 3 clinical trial will show whether plitidepsin decreased days of hospitalization for COVID-19 patients.  The study, expected to be completed in August, will compare plitidepsin’s effectiveness to remdesivir, the current standard of care, which also works by inhibiting replication and can shorten hospitalization for COVID-19 patients by four days, on average. Where remdesivir has fallen short on decreasing the deadliness of the virus, Garcia-Sastre hopes plitidepsin will demonstrate live-saving potential.

The cost of discovery

While doctors have blood thinners and steroids to treat the symptoms of a raging COVID-19 illness, developing a new medicine that specifically targets the virus itself can take many years, explained Bhaven Sampat, an economist and associate professor at the Department of Health Policy and Management at the Mailman School of Public Health at Columbia University.  By repurposing an existing medicine and using already-developed compounds, both Garcia-Sastre and Hazuda shaved precious time off the drug development process. Piggybacking off already identified candidates also helps sidestep some of the cost spent on basic research. “That’s particularly useful because you don’t have to reinvent the wheel in a way,” Sampat said. Remdesivir, so far the only antiviral approved for COVID-19, benefited from the same leg up. Developed nearly a decade ago and shown effective against other coronaviruses including Ebola, SARS and MERS, it was fast tracked for use against COVID-19 and greenlit by the FDA in October 2020.  Another existing drug, ivermectin, may also have potential against SARS-CoV-2. A May meta-analysis suggests it could speed recovery and reduce mortality from COVID-19. The idea is controversial; some experts are unconvinced while proponents are eager to put it to use as a cheap, effective treatment. The anti-parasitic, developed by Merck in the 1980s, is no longer under patent. The company has contended there is not sufficient evidence for its use against COVID. Merck declined to respond to PBS NewHour’s request for comment. Developing a new drug oftentimes costs more than $1 billion dollars, a financial and technological burden typically shared by federally and grant-supported research labs (often at universities), which do basic research to identify drug candidates, and pharmaceutical companies, which bring medicines through expensive clinical trials to market.....

This study was published in medRxiv and was led by Dr Jean-Jacques Rajter a physician at Broward Health Medical Center. The study assessed 280 coronavirus patients over the age of 18, with 173 being treated with the drug and 107 having standard care for the virus. The study found that overall mortality in those who took the treatment was 15% compared to those who did not take it, who had a 25% mortality rate. This would equate to a 40% drop overall. The most notable result in the study showed that the drug had a significant effect on the very high risk group of COVID-19 patients suffering from severe pulmonary disease. Of the patients who did not receive ivermectin, 81% died, while only 39% died when receiving the treatment, improving their survival odds by just over 50%.

Ivermectin was developed in the 1970s as a new class of drug to treat parasitic infections. It was initially used in veterinary medicine before being used to treat onchocerciasis and lymphatic filariasis. 3.7 billion doses are estimated to have been given since its approval. It has also been studied as a potential treatment for influenza and HIV. Dr Peter Hibberd, a board certified emergency medicine physician, said on the trial: “This drug has been used for over 30 years by millions of people around the world and has a marked safety base. We understand fully its side effects, and the effect of a single dose in such a critically diseased state cannot be ignored. That’s why the results were so surprising, because these people had damage in their lungs with a rapidly downhill progression and their clinical course stabilised within 24 to 48 hours.”

Preprint available at medRxiv (June 10, 2020):

https://doi.org/10.1101/2020.06.06.20124461

The study, now withdrawn, deals a blow to the anti-parasite drug’s chances as a COVID treatment, researchers say.  Throughout the pandemic, the anti-parasite drug ivermectin has attracted much attention, particularly in Latin America, as a potential way to treat COVID-19. But scientists say that recent, shocking revelations of widespread flaws in the data of a preprint study reporting that the medication greatly reduces COVID-19 deaths dampens ivermectin’s promise — and highlights the challenges of investigating drug efficacy during a pandemic. “I was shocked, as everyone in the scientific community probably were,” says Eduardo López-Medina, a paediatrician at the Centre for the Study of Paediatric Infections in Cali, Colombia, who was not involved with the study and who has investigated whether ivermectin can improve COVID-19 symptoms. “It was one of the first papers that led everyone to get into the idea ivermectin worked” in a clinical-trial setting, he adds.  The paper summarized the results of a clinical trial seeming to show that ivermectin can reduce COVID-19 death rates by more than 90%1 — among the largest studies of the drug’s ability to treat COVID-19 to date. But on 14 July, after internet sleuths raised concerns about plagiarism and data manipulation, the preprint server Research Square withdrew the paper because of “ethical concerns”. Ahmed Elgazzar at Benha University in Egypt, who is one of the authors on the paper, told Nature he was not given a chance to defend his work before it was removed. Early in the pandemic, scientists showed that ivermectin could inhibit the coronavirus SARS-CoV-2 in cells in laboratory studies2. But data on ivermectin’s efficacy against COVID-19 in people are still scarce, and study conclusions conflict greatly, making the withdrawal of a major trial particularly noteworthy.  Although the World Health Organization advises against taking ivermectin as a COVID-19 treatment outside clinical trials, the over-the-counter drug has become popular in some regions of the world. Some view it as a stopgap until vaccines become available in their areas, even though it has not yet been proven effective; scientists worry that it will also be seen as an alternative to vaccines, which are highly effective.

Ripple effects

The paper’s irregularities came to light when Jack Lawrence, a master’s student at the University of London, was reading it for a class assignment and noticed that some phrases were identical to those in other published work. When he contacted researchers who specialize in detecting fraud in scientific publications, the group found other causes for concern, including dozens of patient records that seemed to be duplicates, inconsistencies between the raw data and the information in the paper, patients whose records indicate they died before the study’s start date, and numbers that seemed to be too consistent to have occurred by chance.  In an editorial note, Research Square said that it has launched a formal investigation into the concerns raised by Lawrence and his colleagues. According to the Egyptian newspaper Al-Shorouk, Egypt’s minister of higher education and scientific research is also examining the allegations. The paper was “withdrawn from the Research Square platform without informing or asking me”, Elgazzar wrote in an e-mail to Nature. He defended the paper, and said of the plagiarism allegations that “often phrases or sentences are commonly used and referenced” when researchers read one another’s papers.  Although dozens of ivermectin clinical trials have been launched over the past year3, the Elgazzar paper was notable for announcing one of the first positive results, as well as for its size — it included 400 people with symptoms of COVID-19 — and the magnitude of the drug’s effect. Few therapies can claim such an impressive reduction in death rates. “It was a significant difference, and that stood out,” says Andrew Hill, who studies repurposed drugs at the University of Liverpool, UK. “It should have raised red flags even then.” Lawrence agrees. “I was absolutely shocked that no one had uncovered it,” he says. Before its withdrawal, the paper was viewed more than 150,000 times, cited more than 30 times and included in a number of meta-analyses that collect trial findings into a single, statistically weighted result. In one recent meta-analysis in the American Journal of Therapeutics that found ivermectin greatly reduced COVID-19 deaths4, the Elgazzar paper accounted for 15.5% of the effect. One of the authors of the meta-analysis, statistician Andrew Bryant at Newcastle University, UK, says that his team corresponded with Elgazzar before publishing the work to clarify some data. “We had no reason to doubt the integrity of [Professor] Elgazzar,” he said in an e-mail. He added that in a pandemic setting, no one can reanalyse all of the raw data from patient records when writing a review. Bryant went on to say that his group will revise the conclusion if investigations find the study to be unreliable. However, even if the study is removed, the meta-analysis would still show that ivermectin causes a major reduction in deaths from COVID-19, he says.

Reliable data needed

The paper’s withdrawal is not the first scandal to dog studies of ivermectin and COVID-19. Hill thinks many of the other ivermectin trial papers that he has scanned are likely to be flawed or statistically biased. Many rely on small sample sizes or were not randomized or well controlled, he says. And in 2020, an observational study of the drug was withdrawn after scientists raised concerns about it and a few other papers using data by the company Surgisphere that investigated a range of repurposed drugs against COVID-19. “We’ve seen a pattern of people releasing information that’s not reliable,” says Hill. “It’s hard enough to do work on COVID and treatment without people distorting databases.” Carlos Chaccour, a global-health researcher at the Barcelona Institute for Global Health in Spain, says it has been difficult to conduct rigorous studies on ivermectin. That’s partly because funders and academics in wealthy countries haven’t supported them, and, he suspects, have often dismissed trials of ivermectin because most of them have been done in lower-income countries. Furthermore, says Rodrigo Zoni, a cardiologist at the Corrientes Cardiology Institute in Argentina, it is difficult to recruit participants because many people — particularly in Latin America — are already taking the widely available drug in an attempt to prevent COVID-19.  Adding to the difficulty are conspiracy theories holding that ivermectin has been proven to work and that drug companies are depriving the public of a cheap cure. Chaccour says he has been called ‘genocidal’ for doing research on the drug rather than just endorsing it. Although the jury is still out on ivermectin, many say the retraction speaks to the difficulty of assessing research during a pandemic. “I personally have lost all faith in the results of [ivermectin] trials published to date,” says Gideon Meyerowitz-Katz, an epidemiologist at the University of Wollongong in Australia who helped Lawrence to analyse the Elgazzar paper. It’s not yet possible to assess whether ivermectin works against COVID-19 because the data currently available are not of sufficiently high quality, he says, adding that he is reading other ivermectin papers in his spare time, looking for signs of fraud or other problems. Chaccour and others studying ivermectin say that proof of whether the drug is effective against COVID-19 rests on a handful of large, ongoing studies, including a trial in Brazil with more than 3,500 participants. By the end of 2021, says Zoni, around 33,000 people will have participated in some kind of ivermectin trial.  “I think it is our duty to exhaust all potential benefits,” says Chaccour, especially given that most countries still do not have widespread access to vaccines. “Ultimately if you do a trial and it fails, fine, but at least we tried.”

Published in Nature (August 2, 2021):

 https://doi.org/10.1038/d41586-021-02081-w

Drugmaker Merck & Co Inc on Thursday said its analysis of available data does not support the safety and efficacy of its anti-parasite drug, ivermectin, for the treatment of COVID-19.  Ivermectin, which is approved in the United States under the brand name Stromectol, is used mainly to treat roundworms, threadworms and other parasites. Officials in the Bolivian city of Trinidad had launched a campaign in May last year to give out free doses of ivermectin to combat the novel coronavirus, although the South American country's health ministry noted the lack of evidence for it as a treatment for COVID-19. (reut.rs/3oVnHsY). The company said its analysis of existing and emerging studies of ivermectin to treat COVID-19 found no scientific basis for a potential therapeutic effect against the respiratory disease caused by the novel coronavirus. (bit.ly/2Mz1NOW). Merck added that there was a concerning lack of safety data in the majority of studies testing ivermectin to treat COVID-19 and cautioned against the use of the drug beyond its use as an anti-parasitic.

Merck statement on Ivermectin use (Feb. 4, 2021):

https://www.merck.com/news/merck-statement-on-ivermectin-use-during-the-covid-19-pandemic/

Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.

Ivermectin is an FDA-approved broad spectrum anti-parasitic agent that in recent years we, along with other groups, have shown to have anti-viral activity against a broad range of viruses in vitro. Originally identified as an inhibitor of interaction between the human immunodeficiency virus-1 (HIV-1) integrase protein (IN) and the importin (IMP) α/β1 heterodimer responsible for IN nuclear import, Ivermectin has since been confirmed to inhibit IN nuclear import and HIV-1 replication. Other actions of ivermectin have been reported, but ivermectin has been shown to inhibit nuclear import of host  and viral proteins, including simian virus SV40 large tumour antigen (T-ag) and dengue virus (DENV) non-structural protein 5....

Published in Antiviral Research (April 3, 2020):

https://doi.org/10.1016/j.antiviral.2020.104787