COVID-19 and Remdisivir, A Path Forward?

I was drawn to the COVID-19 portion of the meeting, since I am located in New York City and — in fact — at Elmhurst hospital where we were nearly overwhelmed by an enormous surge of patients in March, April, and May 2020. We found it difficult to draw any firm conclusions about the investigational therapies that we used because of the volume of patients presenting so quickly. My hope was to find some evidence that others had seen regarding these treatments to help me to understand my own observations. I focused on several of the poster presentations in section B, and here is what I learned from these eight presentations.

First, "Compassionate use of remdesivir in pregnant women with severe COVID-19" by Dr. Richard Burwick of Cedars Sinai. In this study, 86 women, either pregnant or postpartum, received a 10-day course of remdesivir. Although 18 out of 19 women in the postpartum group and 27 out of 67 of the pregnant women required mechanical ventilation or extracorporeal membrane oxygenation, all recovered and were extubated. Remdesivir appeared to be surprisingly effective in this specific group of patients.

Next was “Association between concomitant hydroxychloroquine use and safety and efficacy of remdesivir in severe COVID-19 patients” by Dr. George Diaz of Providence Regional Medical Center Everett. In this randomized, open-label study, the combination of hydroxychloroquine and remdesivir was associated with a worse outcome than remdesivir alone. The two treatment groups, remdesivir over 5 or 10 days as opposed to remdesivir plus hydroxychloroquine, were not well-matched in a number of ways. Significantly more receiving the combination regimen were male, Caucasian, and were receiving high-flow oxygen at entry, but fewer had obesity or cardiovascular disease. Although the study does not support the use of hydroxychloroquine, the lack of randomization in key variables — though understandable — weakens the conclusions.

The third presentation, “Compassionate use of remdesivir in children with severe COVID-19” by Dr. Kathleen Chiotos at the Children's Hospital of Philadelphia, observed 77 children below the age of 18 with an initial oxygen saturation of less than 94% received remdesivir for a maximum of 10 days. Of those, 50% received mechanical ventilation or ECMO. At the time of analysis, approximately 5% of patients in the mechanical ventilation/ECMO group and 5% of the others had expired. Of the first group, 84% had been extubated, and 65% of the non-ventilator group had been discharged. The lack of a control group makes it difficult to evaluate the results. However, the high rate of extubation and the low overall mortality rate are, nonetheless, considerable.

Dr. Renato Maserati presented “Exposure to remdesivir through compassionate use: Safety and efficacy in 163 patients.” This unblinded, multinational analysis demonstrated no significant safety issues related to remdesivir. Of the total patients, 60% received mechanical ventilation or ECMO. Through a mean of 15 days of followup, the overall mortality rate was 20%, but only 47% had documented improvement. This data, although preliminary, provides some support for the role of remdesivir in light of the large proportion of patients who were receiving mechanical ventilation at the time of initiation of therapy. The timing of the use of remdesivir in relation to the phase of the infection is difficult to discern. This antiviral agent might be expected to have its greatest benefit in the early stages, prior to the onset of profound cytokine storm.

Then, Dr. Junzheng Wang’s “Which drugs against COVID-19 could be affordably mass produced and approved for worldwide use?” sought to calculate the generic cost of several potential therapeutic agents. Remdesivir, favipiravir, lopinavir/ritonavir, and emtricitabine/tenofovir could all be supplied for $20 per treatment course or less, though none are currently in adequate supply for broad use in the COVID pandemic. In view of the projected worldwide need for effective treatments, this sort of analysis is helpful in planning for future manufacture and distribution.

In “Efficacy of lopinavir/ritonavir and hydroxychloroquine alone or in combination in patients hospitalized with COVID-19: A non-randomised comparison,” Dr. Roberta Gagliardini discussed the combination of lopinavir/ritonavir and hydroxychloroquine in this open-label, non-randomized analysis, which showed no benefit over either drug alone. Although the study design did not allow for strong conclusions about the value of either of these agents, it is not surprising that combining them did not yield any clear therapeutic benefit.

For “Remdesivir for severe COVID-19 versus a cohort receiving standard of care,” Dr. Susan Olender explained that this study was stronger than others in that it was large and fully randomized, though open-label. On day 14, after initiation of treatment, there appeared to be a clear advantage in the remdesivir both in recovery, 74% as opposed to 59%, and in mortality, 7.6% compared to 12.5%. Though, the COVID-19 treatment history in the non-remdesivir group is not stated. It would be particularly important to know whether dexamethasone or immune plasma was given and to what proportion of patients in each arm.

In the last presentation I focused on, “Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: Experience at a large transplant center in New York City,” Dr. Farah Rahman explained how this study was unique. Especially in how it examined the results of convalescent plasma therapy in a unique group of organ transplant recipients with symptomatic COVID-19 infections. The most important in this small study of 12 patients is the decreasing oxygen requirement seen in six of them on day seven after two units of plasma had been transfused. Plasma studies such as this are difficult to interpret, however. COVID antibody levels in the plasma are not stated, and, perhaps, not known. Although the results seem noteworthy, they would be simpler to interpret if the correlation with antibodies was clear.

Overall, these presentations provided some support to the use of remdesivir in treating COVID-19. Hopefully, we will now learn more about the best time during the course of the infection for this antiviral and how supplies may be increased.

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