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.