Early 3-day remdesivir course may prevent COVID-19 hospitalization, death

An early, 3-day regimen of remdesivir may prevent hospitalization and death in patients with COVID-19 who are at risk for disease progression, according to results of the PINETREE study.

“The risk of COVID-19–related hospitalization or death from any cause by day 28 was 87 percent lower in the remdesivir group than in the placebo group,” noted the authors.

Participants in this multinational, double-blind study were 562 non-hospitalized individuals aged ≥12 years (mean age 50 years, 47.9 percent female, 80.4 percent White, mean BMI 31.0 kg/m²) with COVID-19* who had developed symptoms in the past 7 days (median 5 days pre-infusion) and had ≥1 risk factor for disease progression (age ≥60 years**, obesity, or certain comorbidities). They were randomized 1:1 to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. Mean SARS-CoV-2 RNA nasopharyngeal viral load at baseline was 6.29 log₁₀ copies/mL.

Patients who had previously been hospitalized or received treatment for COVID-19, and those who had received a SARS-CoV-2 vaccine were excluded. The most common comorbidities in this population were diabetes mellitus, obesity, and hypertension at 61.6, 55.2, and 47.7 percent, respectively.

At day 28, COVID-19–related hospitalizations or any-cause death occurred in fewer patients in the remdesivir than placebo group (0.7 percent vs 5.3 percent [n=2 vs 15]; hazard ratio [HR], 0.13, 95 percent confidence interval [CI], 0.03–0.59; p=0.008). [N Engl J Med 2021;doi:10.1056/NEJMoa2116846]

COVID-19–related medically attended visit or any-cause death by day 28 was also lower among remdesivir than placebo recipients (1.6 percent vs 8.3 percent; HR, 0.19, 95 percent CI, 0.07–0.56).

There were no deaths in either group by day 28 and all COVID-19–related hospitalizations took place by day 14.

Any-cause hospitalization occurred in 1.8 and 6.4 percent of patients in the remdesivir and placebo groups, respectively, by day 28 (HR, 0.28, 95 percent CI, 0.10–0.75).

Patient-reported symptoms at baseline were gleaned using the COVID-19–adapted Influenza Patient-Reported Outcome (FLU-PRO) Plus questionnaire (Evidera–PPD). Among those who completed the questionnaire before the first infusion (n=126), 34.8 and 25.0 percent of remdesivir and placebo recipients, respectively, reported symptom alleviation by day 14 (rate ratio [RR], 1.41); the respective percentages were 36.1 and 20.0 percent, respectively, in a post hoc analysis of those who completed the questionnaire on the day of the first infusion (RR, 1.92).

There was no difference in time-weighted average change in nasopharyngeal SARS-CoV-2 viral load between baseline and day 7 between the remdesivir and placebo groups (-1.24 vs -1.14 log₁₀ copies/mL; least-squares mean difference, 0.07).

“[This lack of difference suggests that] SARS-CoV-2 nasopharyngeal viral loads do not reliably predict treatment outcomes in COVID-19,” the authors pointed out.

Adverse event (AE) incidence by day 28 was comparable between remdesivir and placebo recipients (42.3 percent vs 46.3 percent), with treatment-related AEs occurring in 12.2 and 8.8 percent, respectively. The most common (>5 percent) non-serious AEs were nausea, headache, and cough. Serious AEs occurred in fewer remdesivir than placebo recipients (1.8 percent vs 6.7 percent). Grade ≥3 laboratory abnormalities at day 28 occurred in 10.4 and 8.1 percent of remdesivir and placebo recipients, respectively. At day 14, there were minor changes from baseline in creatinine clearance rate in the remdesivir and placebo groups (mean 0.26 and 1.9 mL/min, respectively), as well as in alanine aminotransferase levels (mean -3.0 and -1.0 U/L, respectively).

A treatment for the endemic phase

“[T]hese data show that remdesivir may have greater efficacy when initiated earlier in the course of COVID-19,” remarked the authors, alluding to prior research that showed a decreased risk of progression in patients receiving remdesivir. [N Engl J Med 2020;383:1813-1826]

“Given that remdesivir targets the highly conserved viral RNA-dependent RNA polymerase, it is likely to maintain efficacy against emerging SARS-CoV-2 variants of concern, a potential limitation of neutralizing monoclonal antibody therapy,” they continued.

The authors acknowledged the inability to generalize these data to wider populations as 94.5 percent of patients were US residents and only eight patients were aged <18 years. The trial was also conducted before the delta variant became the dominant strain. Furthermore, the results may not apply to those already vaccinated against SARS-CoV-2.

“However, for patients in regions of the world that do not yet have access to vaccines or for patients who do not have a good response to vaccination (eg, those who are immunocompromised), outpatient remdesivir may play an important role in the management of COVID-19,” they said.

“[G]iven imperfect vaccine uptake and ongoing emergence of variants, it is likely that SARS-CoV-2 will become endemic. Thus, there is a continued need for therapies that can be used early in the disease course to reduce the risk of disease progression, prevent transmission, and be widely distributed to meet global demand,” said Associate Professor Emily Heil and Professor Shyam Kottilil from the University of Maryland, Baltimore, Maryland, US, in an editorial. [N Engl J Med 2021;doi: 10.1056/NEJMe2118579]

The reduction in COVID-19–related hospitalizations and any-cause death with remdesivir corresponded to 47 fewer hospitalizations per 1,000 infections. “[This is] a clinically significant finding in an overwhelmed healthcare system,” they added.

Nonetheless, questions remain, noted the editorialists, one of which is the potential of remdesivir to reduce transmissibility of SARS-CoV-2 given the lack of effect on nasopharyngeal viral load.