Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options

McCreary, Erin K; Pogue, Jason M

Lopinavir is a human immunodeficiency virus (HIV)-1 protease inhibitor administered in fixed-dose combination with ritonavir (LPV/r), a potent CYP3A4 inhibitor that "boosts" lopinavir concentrations. Lopinavir seems to block the main protease of SARS-CoV-1, inhibiting viral replication [22] . In 2003, Chu et al [23] evaluated a series of antivirals for in vitro activity against SARS-CoV-1. They reported lopinavir at 4 µg/mL and ribavirin at 50 µg/mL inhibited SARS-CoV-1 after 48 hours of incubation and that the agents were synergistic when used together [23] . de Wilde et al [24] later described the antiviral activity of lopinavir against SARS-CoV-1 and demonstrated an EC 50 17.1 ± 1 in Vero E6 cells, which is near the upper range of LPV plasma concentrations previously measured in patients with HIV [25] . Sheahan et al [5] evaluated the in vitro efficacy of LPV/r in combination with interferon beta (INFb) against MERS-CoV and found the addition of LPV/r did not significantly enhance antiviral activity of INFb alone (EC 50 = 160 vs 175 IU/mL, respectively). They also described the EC 50 of LPV/r (8.5 µM) and LPV alone (11.6 µM), suggesting similar activity to that described for SARS CoV-1. Despite in vitro activity against MERS-CoV, therapeutic doses of LPV/r + INFb in mice models failed to reduce virus titer and exacerbated lung disease [5] . This is notable because this was the same study in which remdesivir demonstrated both more potent in vitro activity as well as in vivo efficacy. However, the in vivo animal data for MERS-CoV appears equivocal given that a nonhuman primate model demonstrated improved clinical and pathological features after LPV/r treatment [26] . A randomized controlled trial of LPV/r and recombinant interferon-β1b versus placebo is currently enrolling for patients with MERS-CoV, which might help clarify the apparent discrepancy between in vitro and animal models [27] .