A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

Abstract

BACKGROUNDNo therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODSWe conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2 ) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2 ) to the fraction of inspired oxygen (Fio 2 ) of less than 300 mm Hg. Patients 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. The primary end point was the time to clinical improvement, defined as 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. RESULTSA total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. 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). 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). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS

COVID-19 for the Cardiologist

“…A randomized control trial of lopinavir-ritonavir, a combination protease inhibitor designed for HIV treatment, in 199 patients with at least moderate COVID-19 did not significantly alter clinical improvement or viral clearance (131). While the results of this trial were met with disappointment, this negative study should not forestall trials and drug development of protease inhibitors as a therapeutic class, given that this drug was not specifically designed for SARS-CoV2 (128).…”

COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal

“…The first open-label randomized controlled clinical trial of antiviral therapy was recently reported. 3 In this study, 199 patients were randomly allocated to the antiviral agents lopinavir-ritonavir or to standard of care and this regimen was not found to be particularly effective. One reason for this may have been that the patients were enrolled during the pulmonary stage with hypoxia (stage IIb) when the viral pathogenicity may have been only one lesser dominant aspect of the overall pathophysiology, and host inflammatory responses were the predominant pathophysiology We believe that this proposed 3-stage classification system for COVID-19 illness will serve to develop a uniform scaffold to build structured therapeutic experience as healthcare…”

“…Pharmacotherapy targeted against the virus holds the greatest promise when applied early in the course of the illness, but its usefulness in advanced stages may be doubtful. 2,3 Similarly, use of anti-inflammatory therapy applied too early may not be necessary and could even provoke viral replication such as in the case of corticosteroids. 4 It appears that there are two distinct but overlapping pathological subsets, the first triggered by the virus itself and the second, the host response.…”

Coronavirus Disease (COVID-19): A primer for emergency physicians

“…86 A study evaluating lopinavir-ritonavir found no improvement in patient survival or differences in detectable viral RNA. 87 Hydroxychloroquine and azithromycin are also under study. 88 In a single prospective, observational study of 36 patients with COVID-19, those receiving hydroxychloroquine demonstrated higher rates of viral load reduction/disappearance, though no patient centered outcomes were assessed.…”