The results indicate that treatment with either of two small molecule drugs - remdesivir and selinexor - broadly neutralizing antibodies, or cellular immunotherapy may reduce the duration of viral shedding and the intensity of immune responses when administered after peak viral load, at the typical onset of symptoms.
"Our model projects a high likelihood of success for neutralizing antibodies and cellular immunotherapies provided that they achieve adequate potency and are dosed soon after development of symptoms," said the team, based at the vaccine and infectious diseases division of the Fred Hutchinson Cancer Research Center and the University of Washington in the US.
While social distancing has slowed and even eliminated many local COVID-19 epidemics, it is not an economically viable long-term strategy, say the researchers.
“There is no evidence of widespread herd immunity and a vaccine is unlikely to be developed and widely implemented within the next six months. Therefore, second and third waves of infection are likely to occur over the next two years. It is imperative that optimal treatment strategies of COVID-19 are identified urgently to ensure that the case fatality rate is lower during subsequent local epidemics," they stress.
To reduce the impact of the pandemic, lifesaving antiviral therapies must be identified, say Goyal et al. However, the number of clinical trials that can be performed is limited.
Mathematical modeling
To date, said the researchers, selection of antiviral agents has been empirical and guided by limited or absent data. To address that knowledge gap, the team developed mathematical models to project multiple therapeutic approaches.
“The goal of our models is to interpret emerging clinical trial data, and in turn to perfect subsequent trials in terms of selection of antiviral agents, timing of therapy, dosage, treatment duration, avoidance of drug resistance and selection of virologic endpoints.”
The models are based on four datasets of SARS-CoV-2 viral shedding and viral load from 25 infected people: 11 from Singapore, nine from Germany, one from South Korea, and four from France.
They applied the model individually to four separate antiviral therapies: the small molecule drugs remdesivir and selinexor, broadly neutralizing antibodies, and cellular immunotherapy.
The authors conclude that their model “provides a broad platform for assessment of all major types of therapies,” even as they note some important limitations.
“Most critically, [our model] cannot be used to predict trial outcomes but rather establishes important principles to consider when designing and interpreting trials,” they say.
“Overall, our simulations support initiation of therapy soon after symptoms develop.”
'Early test and treat is vital'
The team says that most current clinical trials are focused primarily on hospitalized patients whereas their results and those from two other COVID-19 models suggest that treatment in the days immediately following symptom onset will decrease the duration of detectable viral shedding.
"Our model also predicts that early treatment (before viral peak, usually <5 days post-infection) will limit the extent of the cytolytic immune response required to clear infection. If either of these outcomes are correlates of progression to severe disease as appears to be the case clinically, and transmission risk, then as with HIV, influenza, and Ebola, early test and treat is a vital, currently overlooked strategy."
Source: Science Advances
DOI: DOI: 10.1126/sciadv.abc7112
Title: Potency and timing of antiviral therapy as determinants of duration of SARS-CoV-2 shedding and intensity of inflammatory response
Authors: A Goyal, EF Cardozo-Ojeda, JT Schiffer
