LONDON – Clinical care guidelines recommending the use of the HIV/AIDS combination lopinavir-ritonavir for the treatment of patients hospitalized with COVID-19 must now be updated, say the authors of a paper reporting the full results of a randomized U.K. study showing the antiviral is not effective in this context, published in The Lancet on Oct. 5.

There was no significant difference in the primary endpoint of 28-day mortality, at 22.1% in the lopinavir-ritonavir arm vs. 21.3% for standard of care (p=0.58). The results were consistent in different subgroups of patients. There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay, with 69% in the lopinavir-ritonavir group leaving the hospital within 28 days, compared with 70% of those receiving usual care. Both groups had a median stay of 11 days.

Between March 19 and June 29, 1,616 patients in the Recovery trial were randomized to receive lopinavir-ritonavir while 3,424 patients received usual care alone. Those on lopinavir-ritonavir received 400 mg of lopinavir and 100 mg of ritonavir by mouth every 12 hours for 10 days or until discharge, if sooner. The primary outcome was 28-day all-cause mortality.

Martin Landray, professor of Medicine and Epidemiology at Oxford University, who co-leads the Recovery trial, said, “Treatment of COVID-19 with the drug combination lopinavir-ritonavir has been recommended in many countries. However, results from this trial show that it is not an effective treatment for patients admitted to hospital with COVID-19.”

Since the preliminary results were made public on June 29, the World Health Organization has halted lopinavir-ritonavir treatment groups in its Solidarity trial and reported that the interim results are in line with the U.K. data.

Writing in an accompanying comment, Bin Cao and Frederick Hayden, from the China-Japan Friendship Hospital and Capital Medical University, China, and the University of Virginia School of Medicine, said that compared with the first randomized trial to investigate lopinavir-ritonavir in patients with COVID-19, which they conducted, though the size of the lopinavir-ritonavir group in the Recovery trial was much larger.

“Hence, it provides a more solid evidence base regarding possible lopinavir-ritonavir treatment effects,” Cao and Hayden said. “The findings of these two open-label studies support each other and conclude that lopinavir-ritonavir is not effective in improving outcomes for patients admitted to hospital with COVID-19.”

However, Cao and Hayden said they think there could still be a role for early antiviral treatment for mild cases of COVID-19, and for prophylaxis in high-risk populations after exposure to the virus. “Given the efficient replication of SARS-CoV-2 shortly after infection and the association between mortality and viral RNA loads at diagnosis, it is possible that early use of sufficiently potent antiviral drugs would be an important determining factor in clinical outcomes,” they said.

Peter Horby, professor of Emerging Infectious Diseases and Global Health at Oxford University, and co-chief investigator of Recovery, said, “The result from the Recovery trial is clear. When combined with findings from [Cao’s] earlier, smaller trial and with the WHO interim results, this provides strong evidence that lopinavir-ritonavir is not an effective treatment for patients hospitalized with COVID-19.”

REGN-COV added to Recovery

Although it is disappointing that the HIV/AIDS combination was not effective, Horby said, “These findings have allowed us to focus our efforts on other promising treatments, and have informed the way in which individual patients are treated.”

As one example, on Sept. 27, the Recovery trial began testing Regeneron Pharmaceuticals Inc.’s REGN-COV2, in which it will compare the effects of adding the antibody cocktail to standard of care vs. standard of care alone, in patients hospitalized with COVID-19.

As with other drugs tested in Recovery, this arm of the study will assess the impact of REGN-COV2 on all-cause mortality at 28 days. Other endpoints include reduction in hospital stays and the need for ventilation. At least 2,000 patients will be randomly allocated to the REGN-COV2 arm.

REGN-COV2 is the first therapy specifically developed to treat COVID-19 being evaluated by the Recovery trial, which to date has recruited 13,130 patients. The product was selected based on its emerging safety profile in humans, preclinical data showing it can protect against viral escape mutations, and research in nonhuman primates showing it reduced the amount of virus and associated damage in the lungs.

While previously Recovery has looked at whether existing drugs can be repurposed, it was designed so that as new drugs such as REGN-COV2 become available, they can be tested quickly.

Commenting over the weekend, after news that President Donald Trump had been treated with REGN-COV2, Landray noted several hundred patients with relatively mild disease have been given the drug in phase II studies, which have shown that it is effective in reducing viral load. “But [the trials] have been too small to know whether they improve patient outcomes such as reducing the duration of hospital stay, reducing the need for mechanical ventilation or improving survival,” he said.

“Regardless of how one man with this disease fares, we need evidence from the trials before reaching firm conclusions about this treatment,” Landray said.

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