A Light at the End of the Tunnel: Potential treatments and vaccines
First of all, the numbers: Worldwide, as of this writing, the COVID 19 pandemic has infected over 2.2 million people, and there have been nearly 150,000 deaths as a result. In the USA, those numbers are 680,000 infected and 35,000 dead. Georgia has recorded over 16,000 cases and over 600 deaths. Chatham County has recorded 170 cases and 5 deaths.
That’s the drumbeat we’ve heard, over and over: How many are infected, and how many have died. We all read those figures every day. Meanwhile, we sanitize everything and keep our distance from one another and try to go on with our lives, wondering when this will all end.
Here, in week 5 of the pandemic, I’d like to offer a dollop of hope.
Life will return to some semblance of normal when we can begin to ease the social distancing measures we’ve all grown so accustomed to. That day is coming soon. Nationally, we are past the peak level of infections and deaths from the COVID 19. The statewide peak in Georgia is now projected to be around May 1. About two weeks after that, we can expect to see some relaxation of social distancing, although large gatherings will likely still be banned—and we’ll still have to be careful, exercising the same careful sanitation techniques we’ve all grown accustomed to over the last several weeks. More widely available testing will allow us to follow up on infected persons and their contacts. We’ll all be more vigilant and aware.
But how can it end?
Besides the obvious elements listed above, which will be with us for a while, there are two ways we can mitigate the spread and overall impact of COVID 19. First, antiviral treatments offer us a method for getting rid of the virus in infected persons before it can do much of its damage. An effective antiviral medication can help patients who have COVID 19 stave off the so-called “cytokine storm” phase of the illness, which is where most of the morbidity and mortality come from. Second, an effective COVID 19 vaccine would provide immunity to the virus—and while no vaccine is perfect, vaccination of a large percentage of the population would dramatically limit the virus’s chances of spreading unhindered among us.
The development of antiviral treatments for COVID 19 has been described as “chaotic.” The most effective clinical research involves large-scale placebo-controlled randomized clinical trials (RCTs)—the bigger the better, to allow the statistics to potentially be more representative of the population as a whole. Unfortunately, both worldwide and in the USA, the urgency of the pandemic has led to a fragmented, decentralized approach to research, resulting in the generation of a number of smaller studies which have sometimes yielded conflicting and confusing results. However, there is now some movement towards a more coordinated research effort, particularly in the U.S. Dr. Francis Collins, director of the National Institutes of Health (NIH), the world’s largest biomedical research agency, has been working over the last month to coordinate research efforts among various academic medical centers and several of the larger pharmaceutical companies in an effort to come out with a unified approach to drug testing. Those trials are all in the very early stages. What we have currently is scattershot data from a number of smaller studies, although there are currently around 500 clinical trials of anti-COVID 19 drug treatments worldwide, including over 100 in the USA (https://clinicaltrials.gov/ct2/results/map?cond=COVID-19&map= ).
Here’s what we know now:
Chloroquine and Hydroxychloroquine. These drugs both have been used for decades. Originally developed as antimalarial medications, they have also been used in the treatment of chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Hydroxychloroquine received some early attention in the pandemic when it was referred to by President Trump as a “game changer.”
Both drugs appear to block viral entry into cells. They also have immunomodulating effects, blocking the some of the effects of the cellular inflammatory mediators known as cytokines. Both drugs have shown efficacy in inhibiting SARS-CoV-2 (the virus that causes COVID 19, in vitro (i.e. in a test tube). A clinical trial of the use of chloroquine in 100 Chinese COVID-19 patients in China showed promise, but the data are preliminary the actual trial methodology have not yet been made public. An open-label French study of 36 patients treated with hydroxychloroquine (20 in the hydroxychloroquine group and 16 in the control group) reported improved clearance of virus in the treated group as opposed to those receiving standard care. The addition of azithromycin in 6 of the treated patients resulted in improved viral clearance as compared to hydroxychloroquine monotherapy. Still, this study was small and intrinsically flawed. Numerous other smaller-scale open-label trials of these drugs have shown promise, however, and a large-scale NIH-sponsored clinical trial is now under way (https://www.nih.gov/news-events/news-releases/nih-clinical-trial-hydroxychloroquine-potential-therapy-covid-19-begins). The Duke Clinical Research Institute is testing prophylactic hydroxychloroquine use in 15,000 health care workers (https://dcri.org/hero-pcori-funding-coronavirus/). On March 28, the FDA issued an emergency use authorization for off-label hydroxychloroquine use in COVID 19 patients who do not have access to a clinical trial.
Both hydroxychloroquine and chloroquine have some risks of toxicity, particularly with regard to a risk for cardiac arrythmia. Generally, hydroxychloroquine is generally better-tolerated than chloroquine.
Remdesivir. This antiviral agent was first used clinically against the Ebola virus, where was shown to be effective. Like hydroxychloroquine, it has been shown to inhibit replication of SARS CoV-2 in vitro, and case reports regarding its safe use in COVID 19 patients have been reported. The most significant study of remdesivir to date was a recent study undertaken at the University of Chicago (https://www.businessinsider.com/stat-news-gileads-remdesivir-treats-coronavirus-patients-2020-4). This trial included 125 COVID 19 patients, 113 of whom had severe disease. The trial showed that the majority of treated patients had rapid recovery of fever and respiratory symptoms. Only two of the treated patients died. There is now a large-scale NIH-sponsored clinical trial for remdesivir which is enrolling COVID 19 patients (https://clinicaltrials.gov/ct2/show/NCT04280705 ) Currently, remdesivir is only available through a clinical trial or on compassionate release by its manufacturer, Gilead Sciences.
Farapiravir. This antiviral drug has been used against influenza and Ebola with success. It has been shown to be effective in inhibiting viral replication of SARS CoV-2 in vitro. One randomized, controlled trial showed this medication to have modest activity in inhibiting the COVID 19 virus in infected patients. More studies are planned. It is currently available only via clinical trial.
Other antivirals. Oseltamivir (Tamiflu) is FDA-approved for influenza A but seems to have no efficacy against SARS CoV-2. By contrast, Umifenovir (Arbidol), used in China and Russia for treatment of influenza A, has shown efficacy against SARS CoV-2 both in vitro and in limited clinical trials. Anecdotal data and small clinical trials have shown that azithromycin may have some activity against SARS-C0V-2, as noted above. Larger-scale clinical trials are under way. Interferons have been studied in other coronavirus infections, and interferon-beta was effective against MERS, a virus similar to SARS CoV-2. There are no clinical data which demonstrate efficacy against the COVID 19 virus, however. Nitazoxanide (Alinia) is an antimicrobial with broad antiviral activity which is well-tolerated. It has been shown to have antiviral activity against SARS CoV-2 in vitro, but clinical data are lacking.
Adjunctive therapies. Agents which might affect the outcome of COVID 19 patients but would not cure the viral infection itself have also been studied.
Corticosteroids have been used in critically ill COVID 19 patients with conflicting results. There are major potential side effects to these medications, so their use is generally not recommended unless there is a compelling reason to use them outside of COVID 19 treatment.
Since the later stages of COVID 19 appear to involve a “cytokine storm” of various pro-inflammatory agents, the use of anticytokine agents have been postulated as being useful in critically ill patients with COVID 19. The cytokine IL-6 seems to have a pivotal role in driving the COVID-19 inflammatory response, so monoclonal antibodies against IL-6 may help to attenuate this effect. Tocilizumab (Actemra), an IL-6 receptor antagonist which is FDA-approved to treat RA, has been used in a small series of severely ill COVID 19 patients with early reports of success. Sarilumab (Kevzara) is another monoclonal antibody against IL-6 already approved for use in RA which is being studied in this fashion. Similar agents are also undergoing clinical trials.
The use of hyperimmune globulin derived from the plasma of formerly infected COVID 19 patients may help attenuate the infection in patients who receive it during the first 7-10 days of illness. Preliminary data from China are encouraging, but more research is needed.
The best long-term method for dealing with COVID 19 is the development of a reliable vaccine, which will allow so-called “herd immunity” to blunt the transmissibility of SARS CoV-2 in the general population. There are currently 78 currently active COVID 19 vaccine projects under development worldwide, including four which have entered the human clinical trial phase (https://www.nature.com/articles/d41573-020-00073-5). The drug-maker Moderna started clinical testing of an mRNA-based vaccine only two months after SARS CoV-2 viral sequencing was completed. And although most experts, including Dr. Anthony Fauci of the National Institute for Allergy and Infectious Disease, have stated that a working vaccine would be available in 12-18 months, there are others who are more optimistic. Professor Sarah Gilbert, a vaccine researcher at Oxford University in the UK, recently made international news when she stated that she was “80% certain” that her research group would have a working COVID 19 vaccine ready for use by September 2020. So there is some hope that this will all be over sooner than anyone might have predicted.
The COVID 19 pandemic has been an arduous journey through uncharted public health waters. The social distancing measures which were enacted have been brutally effective, saving hundreds of thousands of lives, but at the cost of millions of jobs and trillions of dollars in lost revenue. Still, as we move past the national peak of cases in this crisis, we are finally able to see a glimmer of light at the end of the proverbial tunnel.
That light, and the hope that it carries with it, is an intrinsically beautiful thing.