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Lopinavir-ritonavir (Kaletra), a protease inhibitor mainly used for HIV, did not reduce mortality or speed recovery from COVID-19, Britain's large affirmed.

Mortality at 28 days was 23% among the hospitalized COVID-19 patients randomized to lopinavir-ritonavir (400 and 100 mg, respectively, for 10 days or until discharge) compared with 22% in the usual care group (rate ratio [RR] 1.03, 95% CI 0.91–1.17).

The same was true for all prespecified subgroups, including sex, age, duration of illness, degree of respiratory support at baseline, and predicted mortality risk, Peter Horby, MD, PhD, of the University of Oxford, England, and colleagues reported in .

Secondary endpoints likewise were similar with lopinavir-ritonavir and usual care:

• Time to hospital discharge among survivors (median 11 days in both groups)

• Proportion discharged alive within 28 days (RR 0.98, 95% CI 0.91-1.05)

• Invasive mechanical ventilation or death for those not intubated at baseline (RR 1.09, 95% CI 0.99-1.20)

RECOVERY, a U.K.-based pragmatic trial in which hospitalized patients are randomized to various open-label treatments, previously turned up the first mortality benefit in COVID-19 with dexamethasone. Other arms include tocilizumab (Actemra), convalescent plasma, REGN-CoV2 combination monoclonal antibodies, and azithromycin, while a hydroxychloroquine arm was terminated.

The 5,040-patient 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 , noted an accompanying editorial.

Those earlier results along with the drug's well-documented adverse effects and drug interactions led to a 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 editorialists 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.

"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," Cao and Hayden 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 hospital with COVID-19.

Limitations of the RECOVERY trial data, Horby and co-authors said, included enrollment of few intubated patients, "as there were difficulties in administering treatment to patients who could not swallow," such as potential to block feeding tubes with crushed tablets and unreliable bioavailability.

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