87% reduction in hospitalization, death reported in PINETREE trial.
Early treatment with the antiviral drug remdesivir was associated with significantly lower need for hospitalization among at-risk, unvaccinated, non-hospitalized patients with Covid-19 in the randomized PINETREE clinical trial.
A three-day course of intravenous remdesivir administered within seven days of symptom onset was associated with an 87% lower risk of hospitalization or death, compared to placebo, among the study cohort of outpatients 12 years of age or older with at least one risk factor for progression to severe Covid-19.
Over 28 days of follow-up, 0.7% of remdesivir-treated patients were hospitalized for Covid-19, compared to 5.3% of patients in the placebo group (hazard ratio, 0.13; 95% CI, 0.03-0.59), PINETREE researcher Robert L. Gottlieb, MD, PhD, of Baylor University Medical Center, Dallas, and colleagues, wrote in The New England Journal of Medicine.
Based on the findings, the researchers estimated that treatment of at-risk patients with remdesivir early in the course of Covid-19 infection would result in 47 fewer hospitalizations per 1,000 patients.
Remdesivir is a nucleotide analogue prodrug that has been shown to inhibit viral RNA-dependent RNA polymerase. It was the first drug approved for the treatment of Covid-19 by the U.S. Food and Drug Administration, but the early indication included only patients requiring hospitalization, largely based on findings from the ACTT-1 clinical trial, which showed a reduced time to clinical improvement of 5 days (10 days versus 15 days).
Several subsequent trials have shown no significant benefit for the antiviral agent in hospitalized patients, including the DisCoVeRy trial, which included patients treated a median of nine days after symptom onset.
“Early treatment of other acute viral infections improves clinical outcomes and reduces mortality,” Gottlieb et al wrote. “We hypothesized that earlier initiation of a short course of remdesivir treatment in outpatient settings would reduce hospitalizations and mortality.”
The PINETREE trial was designed to test this hypothesis.
All patients recruited for the double-blind, randomized, placebo-controlled trial were outpatients with Covid-19 symptom onset occurring within seven days of randomization and treatment who had at least one risk factor for progression to severe disease (age ≥60 years, obesity, and certain co-existing medical conditions).
Remdesivir was given at a dosage of 200 mg on day 1 and 100 mg on days 2 and 3, and the main study endpoint was the composite of Covid-19-related hospitalization or death from any cause by day 28. Adverse events were recorded as secondary endpoints.
A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses, including 279 patients treated with remdesivir and 283 in the placebo group. The mean age of the patients in the study was 50 years, 47.9% of patients were female, and 41.8% were Hispanic or Latino. Common coexisting conditions included diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%).
Among the main findings:
- Covid-19–related hospitalization occurred in two patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% CI, 0.03 to 0.59; P=0.008). No deaths were reported in either group.
- Four of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended medical visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07-0.56).
- Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.
- Mean nasal viral load decreased in both groups over seven days, but the difference between the active treatment and placebo groups was not statistically significant.
The researchers noted that similar discordant findings between clinical efficacy and upper respiratory tract viral load decline were reported in a study involving rhesus macaques infected with SARS-CoV-2.
“These data support the hypothesis that SARS-CoV-2 nasopharyngeal viral loads did not reliably predict treatment outcomes in Covid-19,” they wrote.
In commentary published with the study, Emily Heil, PharmD, and Shyam Kottilil, MD, PhD, of the University of Maryland, Baltimore, wrote that while remdesivir may prove to be an important early treatment for Covid-19, the need for intravenous administration is likely to limit its implementation.
“Access to and uptake of single-dose monoclonal antibodies have been challenging, a fact that does not bode well for a 3-day course of outpatient intravenous remdesivir,” they wrote, adding that while “remdesivir administration requires less monitoring than monoclonal antibody administration, the majority of patients in this trial received remdesivir outside of their home or nursing facility necessitating multiple health care interactions during the time that patients were acutely infected.”
“The findings of this trial reinforce the need for timely access to outpatient therapeutics and support the proof of concept for pursuing oral prodrugs of remdesivir’s active metabolite,” they noted.
“Rapid emergence of variants with adaptive mutations in the spike protein can result in escape from vaccines and monoclonal antibodies, whereas antiviral agents, given the absence of variation in their viral target, are likely to maintain activity, reinforcing the value of antivirals such as remdesivir in curtailing the pandemic. If Covid-19 is here to stay, our focus on prevention through vaccines remains a priority, but therapeutic options to keep vulnerable patients out of the hospital are an important tool in the armamentarium,” concluded Heil and Kottilil.
Study limitations include underrepresentation of some patient groups, ages, and vaccination status; that the study was conducted before the delta variant emerged; and the discontinuation of the study for administrative reasons that led to less than 50% of the planned enrollment being achieved.
- Treatment with the antiviral drug remdesivir was associated with significantly lower need for hospitalization among at-risk, unvaccinated, non-hospitalized patients with Covid-19 and symptom onset within seven days of treatment in the randomized PINETREE clinical trial.
- A three-day course of intravenous remdesivir was associated with an 87% lower risk of hospitalization or death, compared to placebo, among the study cohort of outpatients 12 years of age or older with at least one risk factor for progression to severe Covid-19.
Salynn Boyles, Contributing Writer, BreakingMED™
The PINETREE study was funded by Gilead Sciences; ClinialTrials.gov; NCT04501952.