Study Authors: Peter W. Horby, Marion Mafham, et al.; Bin Cao, Frederick G. Hayden
Target Audience and Goal Statement: Infectious disease specialists, pulmonologists
The goal of this study was to examine the clinical effects of lopinavir-ritonavir, a coformulated HIV-1 protease inhibitor, in patients hospitalized with COVID-19.
Question Addressed:
- Did patients hospitalized with COVID-19 derive a clinical benefit from taking an HIV drug combination?
Study Synopsis and Perspective:
As the COVID-19 death toll ticks upward, well beyond the one million mark, researchers continue to intensify efforts to find effective treatments for both mild and moderate-to-severe disease.
The viral RNA-dependent RNA polymerase inhibitor remdesivir has shown little or no impact on the survival of hospitalized patients with COVID-19, according to a World Health Organization (WHO) trial. The antimalarial hydroxychloroquine fell flat as a treatment and prophylaxis strategy against COVID-19. Only the steroid dexamethasone has been found to help patients with severe COVID-19, defined as patients with high oxygen requirements and need of a ventilator.
Action Points
- Treatment with lopinavir-ritonavir did not reduce 28-day mortality or the risk of progressing to invasive mechanical ventilation in hospitalized patients with COVID-19, according to the randomized RECOVERY trial.
- Note that the results were consistent across all prespecified subgroups, including age, sex, ethnicity, duration of illness, degree of respiratory support at baseline, and predicted mortality risk.
According to results from the U.K.-based RECOVERY trial, recently published in The Lancet, lopinavir-ritonavir did not reduce mortality or speed up recovery from COVID-19.
Mortality at 28 days was 23% among the hospitalized COVID-19 patients randomized to lopinavir-ritonavir compared with 22% in the usual care group (rate ratio [RR] 1.03, 95% CI 0.91–1.17), reported Peter Horby, MD, PhD, of the University of Oxford in England, and colleagues.
RECOVERY -- one of the world's largest efforts to find effective COVID-19 treatments currently underway at 176 U.K. hospitals -- was the first large-scale randomized clinical trial to report the effects of lopinavir-ritonavir in patients hospitalized with COVID-19. The results also confirmed those of an earlier smaller trial from China that showed no improvement in viral load, duration of hospital stay, or mortality with the combination in patients hospitalized with COVID-19.
"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," said Martin Landray, MBChB, PhD, of the Nuffield Department of Population Health at the University of Oxford, who co-leads the RECOVERY trial. "Since our preliminary results were made public on 29 June, the WHO has halted lopinavir-ritonavir treatment groups involved in its SOLIDARITY trial and reported that their interim results are in line with those presented here."
In this randomized, controlled, open-label, platform trial, patients admitted to the hospital with COVID-19 (mean age 66.2 years) were randomized to receive lopinavir-ritonavir (n=1,616) or usual care (n=3,424). Patients in the active intervention arm received 400 mg of lopinavir and 100 mg of ritonavir orally every 12 hours for 10 days or until discharge, if sooner.
The primary outcome was 28-day all-cause mortality. Time to discharge from hospital and cause-specific mortality were included among the numerous secondary and prespecified subsidiary clinical outcomes.
In addition to the main outcome, the risk of needing a ventilator did not differ between the groups, with 10% of those on lopinavir-ritonavir requiring ventilation versus 9% of those who received usual care.
Both groups had a median hospital stay of 11 days and also had a similar probability of being discharged alive from the hospital within 28 days (RR 0.98, 95% CI 0.91-1.05).
The researchers noted that the results were consistent across all prespecified subgroups, including age, sex, ethnicity, duration of illness, degree of respiratory support at baseline, and predicted mortality risk.
Study limitations included the absence of information on non-serious adverse reactions/reasons for stopping treatment, as well as physiological, laboratory, and virological parameters. In addition, very few intubated patients were enrolled, "as there were difficulties in administering treatment to patients who could not swallow."
Source References: The Lancet 2020; DOI: 10.1016/S0140-6736(20)32013-4
Editorial: The Lancet 2020; DOI: 10.1016/S0140-6736(20)32078-X
Study Highlights and Explanation of Findings:
Among RECOVERY trial participants hospitalized with COVID-19, there were no differences between patients assigned to lopinavir-ritonavir versus usual care in the primary outcome of 28-day all-cause mortality or key secondary clinical outcomes, including duration of hospital stay and the proportion of patients discharged alive from the hospital within 28 days.
The trial "provides a more solid evidence base regarding possible lopinavir-ritonavir treatment effects" than the prior 199-patient trial from China, with similar findings and interim results from the WHO Solidarity trial, noted Bin Cao, MD, of the National Clinical Research Center for Respiratory Diseases in Beijing, and Frederick Hayden, MD, of the University of Virginia School of Medicine in Charlottesville, in an accompanying editorial.
Those earlier results along with the drug's well-documented adverse effects and drug interactions led to a National Institute of Health recommendation against lopinavir-ritonavir use for hospitalized COVID-19 patients outside of clinical trials.
The many other clinical care guidelines that have recommended lopinavir-ritonavir should now be updated, Horby's group urged.
Still, early antiviral treatment could be worth testing for mild cases of COVID-19 or post-exposure prophylaxis in high-risk populations, noted Cao and Hayden.
"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, although few early intervention trials have been completed," they wrote.
Also, they argued, antiviral and immunomodulator combinations should be studied, since monotherapy might not be enough for moderately to severely ill patients admitted to the hospital with COVID-19.
"The result from the RECOVERY trial is clear. When combined with findings from an 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," said Horby in a statement. "Whilst it is disappointing that there was no significant benefit from lopinavir-ritonavir for patients in hospital, these findings have allowed us to focus our efforts on other promising treatments, and have informed the way in which individual patients are treated."
Primary Source
The Lancet
Secondary Source
The Lancet
Source Reference: Cao B, Hayden FG "Antiviral monotherapy for hospitalised patients with COVID-19 is not enough" Lancet 2020; DOI: 10.1016/S0140-6736(20)32078-X.
Additional Source
MedPage Today
Source Reference: Phend C "Kaletra Again Fails for Moderate-to-Severe COVID-19" 2020.
https://www.medpagetoday.org/infectiousdisease/covid19/89216
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