Four repurposed antivirals show no benefit for COVID-19 mortality

The four original drugs tested in the WHO Solidarity trial – remdesivir, lopinavir, hydroxychloroquine, and interferon beta-1a – have shown no benefit on mortality, initiation of ventilation, or duration of hospitalization in patients hospitalized with COVID-19, interim trial results show.

This multinational (405 hospitals in 30 countries), open-label trial included 11,330 adult patients hospitalized with COVID-19. They were randomized to receive either remdesivir (n=2,750), hydroxychloroquine (n=954), lopinavir without interferon (n=1,411), interferon (2,063 including 651 who received interferon plus lopinavir), or no trial drug (4,088), in addition to local standard of care (control).

Of these, 11,266 patients were included in the intention-to-treat analysis (62 percent male, 19 percent aged ≥70 years). Sixty-three and eight percent were receiving supplemental oxygen and ventilation, respectively, at randomization, and 38 percent had already been hospitalized for ≥2 days. Twenty-five and 21 percent had diabetes and heart disease, respectively.

A total of 1,253 in-hospital deaths were reported, with death occurring at a median day 8. The 28-day mortality rate was 11.8 percent. The mortality rate was higher among patients who were receiving ventilation at time of randomization (39.0 percent) and lower (9.5 percent) otherwise, as well as among patients aged ≥70 years (20.4 percent) than those <50 years (6.2 percent). [N Engl J Med 2021;384:497-511]

Mortality rate did not significantly differ between patients who received remdesivir and its standard of care control (number of deaths: 301 vs 303; rate ratio [RR], 0.95, 95 percent confidence interval [CI], 0.81–1.11; p=0.50). Similarly, there was no significant difference in mortality rate between patients who received hydroxychloroquine and its control (104 vs 84; RR, 1.19, 95 percent CI, 0.89–1.59; p=0.23), lopinavir* and its control (148 vs 146; RR, 1.00, 95 percent CI, 0.79–1.25; p=0.97), or interferon and its control (243 vs 216; RR, 1.16, 95 percent CI, 0.96–1.39; p=0.11).

“No trial drug had any definite effect on mortality, either overall (each p>0.10) or in any subgroup defined according to age, ventilation status at entry, other entry characteristics, geographic region, or glucocorticoid use,” the authors said.

Initiation of mechanical ventilation after randomization was not reduced with any of the trial drugs vs the respective controls (remdesivir: 295 vs 284; hydroxychloroquine: 75 vs 66; lopinavir: 126 vs 121; and interferon: 209 vs 210).

“The similarity of this null effect for all four drugs is further evidence that none has any material effect on major disease progression,” the authors pointed out.

“[In addition,] each of the three trial treatments that were scheduled to last more than 7 days [remdesivir, hydroxychloroquine, and lopinavir] increased the percentage of patients remaining in the hospital at day 7,” they said.

Discharge from hospital was delayed by about 1–3 days with each drug during active treatment. However, there is the possibility that some patients were kept back for continuous treatment despite recovery. The similarity between the regimens suggests that none “substantially reduced time to recovery.”

Remdesivir: Is there still light?

The hydroxychloroquine, lopinavir, and interferon regimens were discontinued for futility on June 19, July 4, and October 16, 2020, respectively.

“[T]he Solidarity trial sends the clear message that these drugs as currently used should no longer be considered viable treatment options for COVID-19 … [however,] the case for the continued use of remdesivir is more nuanced,” said Professor David Harrington from the Harvard T.H. Chan School of Public Health and the Dana-Farber Cancer Institute, Boston, Massachusetts, US, and co-editorialists. [N Engl J Med 2021;384:576-577]

While there was no mortality benefit with remdesivir observed in the Solidarity trial, other trials such as the Adaptive Covid-19 Treatment Trial, showed a potential reduction in recovery time with remdesivir, though no mortality benefit, they said. [N Engl J Med 2020;383:1813-1826] Other trials showed an improvement in clinical status with remdesivir though this was dependent on treatment duration, while others showed that the shortened recovery time was dependent on time of treatment initiation. [JAMA 2020;324:1048-1057; Lancet 2020;395:1569-1578]

“Even without a reduction in in-hospital mortality, reducing the time to recovery and hospital discharge among patients who survive is important, both for patients and for stressed healthcare systems,” they added.