Results from the first randomized controlled trial of antiviral against SARS-CoV-2

This COVID-19 perspective was produced by Professor Jens D. Lundgren – one of the world’s leading infectious disease specialists. Jens. D. Lundgren is currently leading a clinical trial of investigational vaccine designed to protect against COVID-19. Jens D. Lundgren is also the founder and member of the steering committee of the HIV in Europe Initiative and in 2015 he was awarded the EACS Award for Excellence in HIV Medicine.

Friday 20th March 2020
So, yesterday, the first randomized controlled trial of an antiviral against SARS-CoV-2 infection was published^{. 1} The drug in question was the well known HIV protease inhibitor lopinavir, the plasma concentration of which is boosted by co-administration of the CYP P450 enzyme inhibitor ritonavir. The trial focused on patients with advanced and serious COVID disease – namely those with pneumonia and reduced ability to saturate blood with oxygen. It was designed as an open-label comparison of the antiviral in combination with standard-of-care compared with standard of care alone.

No discernible clinical beneficial effect was observed (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). The study had insufficient power to assess mortality (19% vs 25%, respectively (difference: 5.8% (95% CI: -17 to +6%). No clear effect on viral RNA detection levels were made, although the surrogacy of this for possible clinical benefit is unknown. A total of 14% of those allocated to lopinavir/r stopped prematurely because of adverse drug reactions.

Analysis
The trial appaers reasonable well conducted, not withstanding the open-label which may have caused some degree of bias in endpoint ascertainment. The sample size was relatively limited (n=199), and hence marginal to adequately rule out a possible clinical benefit overall and clearly in relation to mortality. The results will dampen interest to persue this type of antiviral intervention, at least for use in advanced COVID.

The viral kinetics of symptomatic mild SARS-CoV-2 is by now fairly well established. Pre-symptomatically, patients starts to sheet virus from the upper respiratory tract – peak levels around time of onset of symptoms. In patients with mild course of COVID, virus shedding gradually decline and disappears one to three weeks after symptom relief.

Conversely, it is plausible (read: very likely) that viral replication continues to increase for patients with gradually worsening pneumonia, but from that compartment. Further kinetic studies are essential to further validate this. The main reason is that we may have to reconsider timing on starting antiviral therapy and focus on earlier stages of disease, and before manifest and overt pneumonia has developed.

A new trial of remdesivir that examines a possible role in early stages of COVID is being designed and hopefully soon implemented.

Of note, (hydroxy)cloroquine is an anti-malaria-drug without any proven clinical benefit against SARS-CoV-2 infection and hence should not be used outside of clinical trials.

Finally, in 2017 I was part of a National Academies of Science committee that evaluated the research coming out of the west African Ebola virus outbreak.²

A few key highlights of the recommendations from this committee:

• The committee concludes that the randomized controlled trial (RCT) was an ethical and appropriate design to use, even in the context of the Ebola epidemic, stating that RCTs are the most reliable way to identify the relative benefits and risks of products being studied. Except when rare circumstances are applicable, every effort should be made to implement RCTs during epidemics. Randomization can take many forms (e.g., individual randomization, cluster randomization, adaptive trial designs), and trial teams conducting research during future epidemics will need to assess the specific context in order to determine the best trial design.
• Collection of patient-level data, which provides critical clues to better patient management, also was a challenge, due to poor health infrastructure and a shortage of health care personnel.
• The committee found that the success of clinical research is dependent on the community’s understanding of, engagement in, and sense of involvement and respect in the process of planning and conducting research.
• Emerging infectious disease outbreaks can quickly become globalized, calling for a global solution. Better coordination of international research efforts taking place sooner could have led to a safe and effective medicine that might have been deployed during the epidemic—and at the outset of the next one.
• Coordination of international research efforts must continue after an outbreak begins. To that end, the international coalition of stakeholders should convene an independent rapid research response workgroup with the expertise to appraise and prioritize products for trial, determine which trial designs are best suited for the circumstances, and monitor and evaluate the trials. This workgroup would include national leadership and community representatives from affected countries and ensure that resources are allocated efficiently and effectively, that the goals of the response and research activities are clear and agreed upon, and that community engagement and communication strategies are aligned.

Sources
1. Bin Cao, M.D., Yeming Wang, M.D., Danning Wen, M.D., Wen Liu, M.S., Jingli Wang, M.D., Guohui Fan, M.S., … & Chen Wang, M.D. (2020). A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine. 2. National Academies of Science committee. (2017). Clinical Trials During the 2014-2015 Ebola Outbreak. Retrieved from: https://www.nationalacademies.org/our-work/clinical-trials-during-the-2014-2015-ebola-outbreak).