RECOVERY trial findings don’t support use of lopinavir-ritonavir in hospitalized patients

Lopinavir-ritonavir (Kaletra) failed to hasten recovery or reduce mortality for inpatients with Covid-19, according to results from the RECOVERY trial.

Mortality at 28 days was 23% among the hospitalized Covid-19 patients randomized to the HIV protease inhibitor plus usual care versus 22% in the usual care-alone group (rate ratio 1.03, 95% CI 0.91-1.17), reported Peter W. Horby, MD, PhD, and Martin J. Landray, MBChB, PhD, both of the RECOVERY Central Coordinating Office in Oxford, England, and co-authors.

Additionally, there were no differences in secondary endpoints, including time to hospital discharge for survivors and a composite endpoint of invasive mechanical ventilation (IMV) or death for those who were not intubated at baseline, they wrote in the Lancet.

These findings held true in prespecified subgroups of sex, age, duration of illness, degree of baseline respiratory support, and predicted mortality risk, the authors noted.

“Many clinical care guidelines have recommended lopinavir-ritonavir for treatment of patients admitted to hospital with Covid-19. These guidelines should be updated,” they stated.

With over 5,000 patients, these results offer “a more solid evidence base regarding possible lopinavir-ritonavir treatment effects,” versus findings from a study out of Wuhan, China or those from the ongoing World Health Organization Solidarity trial, noted Bin Cao, MD, PhD, of China-Japan Friendship Hospital in Beijing, and Frederick Hayden, MD, of the University of Virginia School of Medicine in Charlottesville, in a comment accompanying the study.

They pointed out that “Treatment of Covid-19 with lopinavir-ritonavir has been recommended as a first-line or second line in many countries,” but “The results from the RECOVERY trial show that lopinavir-ritonavir monotherapy is not an effective treatment for patients admitted to hospital with Covid-19.” In July 2020, the NIH recommended against using lopinavir-ritonavir for hospitalized Covid-19 patients outside of clinical trials.

Still, Cao and Hayden noted that early antiviral treatment or post-exposure prophylaxis in high-risk populations may still be viable for mild cases of Covid-19.

“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, adding that antiviral and immunomodulator combinations should be studied because monotherapy may be insufficient for moderately to severely ill Covid-19 patients in the hospital.

RECOVERY is a U.K.-based pragmatic trial in which hospitalized patients with SARS-CoV are randomized to various open-label treatments. Interim results from RECOVERY in March 2020 demonstrated a mortality benefit in Covid-19 with dexamethasone, the steroid that President Trump is currently receiving.

Other agents being investigated in RECOVERY are tocilizumab (Actemra), convalescent plasma, REGN-CoV2 combination monoclonal antibodies, and azithromycin. The trial’s hydroxychloroquine arm was terminated after showing that the immunosuppresant was not tied to reductions in 28-day mortality but was instead linked with an increased risk of progressing to invasive mechanical ventilation or death.

For the current study, 1,616 patients (mean age 66.2 years; majority white men) were randomly allocated to receive lopinavir-ritonavir and 3,424 patients were assigned to receive usual care from March through June 2020. The study drug dosing regimen consisted of oral 400 mg and 100 mg, respectively, for 10 days or until discharge, or to one of the other RECOVERY treatment groups.

“At randomization, about a quarter of patients had no ventilatory support, most were receiving oxygen only, and a very small proportion were on invasive mechanical ventilation,” the authors wrote.

Horby, Landry, and co-authors reported the following for the secondary outcomes:

  • Time to hospital discharge for survivors: median 11 days for both study groups.
  • Time until discharge alive from hospital within 28 days: RR 0.98 (95% CI 0.91-1.05).
  • IMV or death for those without baseline intubation: RR 1.09 (95% CI 0.99-1.20).

Limitations of the current study included a small number of intubated patients, “as there were difficulties in administering treatment to patients who could not swallow,” according to the authors. In addition, “It is unclear whether the dose of lopinavir-ritonavir we used achieved adequate SARS-CoV-2 inhibitory concentrations in the lungs,” they explained, citing a pharmacology study from August 2020 that stated “The doses [ of lopinavir-ritonavir] required to provide optimal inhibition are obviously impracticable due to unacceptable risk of toxicity.”

Nonetheless, the authors emphasized that “lopinavir-ritonavir does not improve clinical outcomes for patients admitted to hospital with Covid-19.”

Whether clinicians will accept the RECOVERY findings as the final word on this treatment regimen is another matter. In multiple letters to the editor in the May 2020 New England Journal of Medicine, physicians took issue with results from the Wuhan study, performed by Cao and colleagues, arguing that “the trial was statistically underpowered to show this outcome [time until clinical improvement];” that “Antiviral drugs are most effective when they are administered early in an infection, yet the patients in this trial underwent randomization a median of 13 days after disease onset;” that “patients who received lopinavir-ritonavir [had] a shorter stay by 5 days in the intensive care unit;” and that “Lopinavir-ritonavir… is available for immediate clinical use in many countries. Because there currently are no approved treatments for Covid-19… we should not yet abandon lopinavir-ritonavir… pending completion of the World Health Organization SOLIDARITY trial.”

Whether developer AbbVie will continue to support the drug combo in Covid-19 care after RECOVERY results is unknown. In June 2020, after the disappointing Wuhan results, the company teamed up with Harbour BioMed, Utrecht University, and Erasmus Medical Center, both in the Netherlands, to develop a new antibody to prevent and treat Covid-19, according to Fierce Biotech.

  1. Treatment with lopinavir-ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death in hospitalized Covid-19 patients.
  2. The study authors suggested that clinical guidelines should be updated to reflect these findings from the RECOVERY trial.

Shalmali Pal, Contributing Writer, BreakingMED™

RECOVERY is funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR), and supported by the University of Oxford, UK Research and Innovation, NIHR Oxford Biomedical Research Centre, Wellcome Trust, the Bill & Melinda Gates Foundation, the UK Department for International Development, Health Data Research UK, the MRC Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support.

AbbVie contributed some supplies of lopinavir-ritonavir for study use. Roche contributed tocilizumab for study use.

Horby and Landry reported no relationships relevant to the contents of this paper to disclose. Co-authors reported support from the UK MRC, an NIHR Senior Research Fellowship, and the NIHR Nottingham Biomedical Research Centre.

Cao reported a relationship with Horby for influenza and COVID-19 therapeutic studies. Hayden reported relationships with the University of Alabama Antiviral Drug Discovery and Development Consortium, Wellcome Trust, Arcturus, Cidara, Fujifilm, Gilead Sciences, GlaxoSmithKline, Merck, Pardes Biosciences, Regeneron, resTORbio, Ridgeback Biotherapeutics, SAB Biotherapeutics, Takeda, Vir, and Cytodyn/University of Virginia School of Medicine.

 

Cat ID: 190

Topic ID: 79,190,254,930,570,190,926,192,927,151,928,925,934