Protease inhibitors could benefit from being trialled with milder cases of COVID-19

AbbVie was one of the first companies to donate its combination of HIV protease inhibitors Aluvia (lopinavir/ritonavir), also known as Kaletra, to help China treat patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, more recent investigations show that treatment with lopinavir-ritonavir does not actually provide a substantial benefit beyond standard care*, says GlobalData, a leading data and analytics company.

Angad Lotay, MPharm, Infectious Diseases Analyst at GlobalData, comments: “In the latest evidence from the LOTUS clinical trial, it was noted that patients recruited were likely ‘more ill’ (severely ill) than the typical COVID-19 patient and it is therefore possible that the body’s inflammatory response was the main driver of the disease – implying that the disease was simply too advanced to have benefited from any protease inhibition.”

In the LOTUS clinical trial, a total of 199 patients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either lopinavir/ritonavir (n=99) or standard-care alone (n=100). The study found that treatment with lopinavir and ritonavir showed no clinical improvement in ‘seriously ill’ patients with COVID-19 when compared to standard care alone.

Lotay adds “The trial was initiated in rapid response to the COVID-19 emergency and, therefore, treating/testing severely ill patients could have been a reflex reaction. Additional studies that target a mild severity of COVID-19 patients could provide more a more accurate indication to whether protease inhibitors work. With 80% of global cases being diagnosed as mild, recruitment should not be scarce.”

Scientists conducting an in vitro study at Johnson & Johnson (J&J) found that darunavir, branded as Prezista also failed to show activity against SARS-CoV-2. In addition to this, similar results were reported following the randomized controlled trial of darunavir and cobicistat (DRV/c) in treating 30 laboratory-confirmed COVID-19 patients. J&J have since publicly spoken about the lack of evidence for the drug as a COVID-19 treatment in an official statement.

Lotay concludes “Targeting the correct patient population/severity group is vital in order to draw more conclusive evidence. It may be a case that protease inhibitors just do not work against the coronavirus when used alone, however, additional clinical trials are being conducted with adjuvant treatment such as interferon-alpha, chloroquine, and remdesivir to name a few. Although current evidence on the efficacy and safety of any protease inhibitor for treating COVID-19 infection is limited, future investigations could provide some hope however, targeting the correct patients and conducting the trial with a robust investigational approach is needed for a treatment to be deemed successful in COVID-19.”

*According to the results of the LOTUS Chinese clinical trial, published in the New England Journal of Medicine (Chinese Clinical Trial Register number: ChiCTR2000029308)

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