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Lopinavir-Ritonavir Shows No Significant Benefit in Treating COVID-19

A recent randomized, clinical trial didn’t find any significant benefit form treating COVID-19 with lopinavir-ritonavir. Find out why Chinese researchers thought the HIV drug combination showed promise for treating viruses similar to COVID-19 and what happened when it was used in patients infected with the novel coronavirus.

BEIJING, CHINA – The search continues for therapeutics to effectively treat severe illness caused by SARS-CoV-2, even with a disappointing result from a trial using an HIV drug combination.

A study published in the New England Journal of Medicine found no benefit with lopinavir–ritonavir treatment of the novel coronavirus beyond standard care. The randomized, controlled, open-label trial focused on hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19.

Background information in the report points out that, after the emergence of severe acute respiratory syndrome (SARS) in 2003, screening of approved drugs identified lopinavir, a human immunodeficiency virus (HIV) type 1 aspartate protease inhibitor, as having in vitro inhibitory activity against SARS-CoV, the virus that causes SARS in humans. Ritonavir is combined with lopinavir to increase its plasma half-life through the inhibition of cytochrome P450. The authors note that an open-label study published in 2004 suggested, by comparison with a historical control group that received only ribavirin, that the addition of lopinavir–ritonavir (400 mg and 100 mg, respectively) to ribavirin reduced the risk of adverse clinical outcomes (acute respiratory distress syndrome [ARDS] or death) as well as viral load among patients with SARS.

“ However, the lack of randomization and a contemporary control group and the concomitant use of glucocorticoids and ribavirin in that study made the effect of lopinavir–ritonavir difficult to assess,” according to the researchers. “Similarly, lopinavir has activity, both in vitro and in an animal model, against Middle East respiratory syndrome coronavirus (MERS-CoV), and case reports have suggested that the combination of lopinavir–ritonavir with ribavirin and interferon alfa resulted in virologic clearance and survival. However, because convincing data about the efficacy of this approach in humans are lacking, a clinical trial (with recombinant interferon beta-1b) for MERS is currently under way.”

Patients in the Chinese study had an oxygen saturation (Sao₂) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao₂) to the fraction of inspired oxygen (Fio₂) of less than 300 mm Hg.

The participants were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. Defined as the primary end point was the time to clinical improvement, i.e., the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

With 199 patients with laboratory-confirmed SARS-CoV-2 infection undergoing randomization, 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group.

Results indicate that treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). esearchers report that mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7).

In addition, the percentages of patients with detectable viral RNA at various time points were similar, according to the report.

In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by one day than what researchers observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). The study team determined that gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group.

Adverse events led to the discontinuation of lopinavir–ritonavir treatment in 13 patients (13.8%) because of adverse events.

“In hospitalized adult patients with severe COVID-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care,” the authors write. “Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit.”