2.1 Lopinavir/Ritonavir
Lopinavir/ritonavir (Kaletra™), an orally administered co-formulated ritonavir-boosted protease inhibitor (PI), can be coalesced into another antiretroviral drugs for the treatment of HIV-1 infection in adults, adolescents and children (Croxtall & Perry, 2010). For good tolerability, the co-administration of lopinavir with a low boosting dose of ritonavir can increases its bioavailability by reducing its hepatic clearance, therefore allowing for lower therapeutic dosages (Scott, 2005). Lopinavir functions by inhibiting the activity of HIV protease enzymes, which prevents the cleavage of polyproteins, leading to the result of immature, non-infectious HIV particles. Meanwhile, ritonavir inhibits CYP3A metabolism and increases the half-life of lopinavir when used in combination, which results in elevated levels, boosting its inhibition of HIV protease (Porche, 2001). Previous studies show that Lopinavir/ritonavir can inhibit the replication of coronavirus to a certain extent (Chu et al., 2004; Götz et al., 2016). Chinese scholars found that the combination of Lopinavir/ritonavir and interferon-β for the treatment of MERS-CoV is better than the control in an infectious marmoset animal model (Chan et al., 2015). During the SARS epidemic in 2003, studies found that 41 SARS patients, who took the treatment of the Lopinavir/ritonavir - ribavirin combination, had reduced ARDS or a lower risk of death compared with 111 SARS patients treated with ribavirin (Chu et al., 2004). In 2016, King Abdullah International Medical Research Center launched a placebo-controlled clinical trial (NCT02845843), the regimen as follows: Lopinavir /Ritonavir (400mg +100 mg/ml) twice a day for 14 days and Interferon β -1b (0.25 mg) subcutaneous once every other day for 14 days. The result showed that the combination of Lopinavir/ritonavir and interferon-β can ameliorate the patients’ condition with MERS-CoV. A clinical randomized controlled study on the efficacy and safety of Lopinavir/ritonavir combined with interferon-β (ChiCTR2000029308) in patients with COVID-19 infection is currently underway.
Researchers have also focused on the therapeutic effect of Lopinavir/ritonavir on COVID-19 based on related literature on Lopinavir/ritonavir for the treatment of MERS-CoV and SARS-CoV. Lopinavir/ritonavir has been proposed as a potential treatment of COVID-19 (Kim et al., 2020; Michele, Maria Anna Rachele De, & Giovanni Nicola, 2020; Nutho et al., 2020). The administration protocol for Lopinavir/Ritonavir for one treatment case was two tablets oral bid (lopinavir 200 mg/ritonavir 50 mg) starting from the early stage of the disease (day 10 of illness). Quantitative reverse transcription (RT) -PCR results showed that the coronavirus load of the patient decreased from the second day of administration, and no detectable or very small titer of coronavirus was observed thereafter (Lim et al., 2020). This case suggested that the COVID-19 may induce relatively mild symptoms and the patient can recover after an early diagnosis of pneumonia by taking Lopinavir/ritonavir (D. Chang et al., 2020; Q. Li et al., 2020; Rothe et al., 2020). Therefore, Lopinavir/ritonavir can be recommended for COVID-19 pneumonia (elderly patients or patients with underlying diseases) from the early stage. However, there should be more evidence needed from well-controlled clinical trials to demonstrate the clinical efficacy of Lopinavir/ritonavir.
An enzyme named 3-chymotrypsin-like protease (3CLpro) is is of uttermost importance in the processing of SARS-CoV-2 viral RNA. The action of 3CLpro could be inhibited by Lopinavir/ritonavir, a protease inhibitor that could thereby disrupt the the virus from replicating and releasing from the host cell (Anand, Ziebuhr, Wadhwani, Mesters, & Hilgenfeld, 2003). As a commonly-used treatment for COVID-19, patients take Lopinavir/ritonavir with food, 400 mg/100 mg twice a day, for 14 days (Cao et al., 2020; Chan et al., 2020). The commonest moderate to severe adverse reactions for the drugs are abnormal stools, diarrhea, weakness, headache, and nausea. The adverse reactions may be exacerbated due to the viral infection for patients with COVID-19. As showed in recent research, almost half of the patients who took Lopinavir/ritonavir therapy experienced a side-effect and 14% of them got so bothered by gastrointestinal adverse effects as to discontinue therapy (Cao et al., 2020). The drug interactions and potential side-effects indicated that Lopinavir/ritonavir in COVID-19 treatment need more clinical trial data and more supporting evidence.