This is the first study to retrospectively compare the clinical safety and efficacy of antiviral monotherapies (chloroquine, arbidol (Umifenovir) or lopinavir/ritonavir) in non-severe, hospitalised COVID-19 patients. We found that patients treated with lopinavir/ritonavir demonstrated longer viral shedding intervals and hospitalisation durations, as well as increased hospitalisation costs and adverse effects. Additionally, chloroquine and arbidol demonstrated decreased viral shedding intervals and hospitalisation durations, together with reduced hospitalisation costs. The chloroquine group demonstrated a reduced median viral shedding interval and hospitalisation duration, while the arbidol group showed a lower cost of hospitalisation and rate of adverse effects.
Despite the SARS-CoV-2 outbreak currently being under control in China, the situation remains dire in other countries [2]. Currently, there is no proven, effective antiviral therapy for COVID-19 patients. Identifying a drug that effectively reduces viral load may improve patient outcomes [11]. New drug development takes time, and developing an antiviral drug specifically for COVID-19 over the short term seems highly unlikely. Focusing on the potential of existing antiviral drugs is the most feasible strategy. Hence our willingness to share our experiences, in an effort to determine a potential anti-SARS-CoV-2 therapy.
In previous studies, lopinavir/ritonavir demonstrated in-vitro antiviral activity against SARS-CoV [7]. Additionally, historical control groups demonstrated that compared to ribavirin monotherapy, a ribavirin and lopinavir/ritonavir combination reduced the risk of adverse outcomes in patients with SARS [7]. However, Cao et al. [12] recently advised that no benefit was demonstrated when using lopinavir/ritonavir therapy, compared with other treatments in critical COVID-19 patients. Similarly, in this study, we failed to demonstrate any superiority in outcomes when using lopinavir/ritonavir monotherapy, in non-severe COVID-19 patients. This may be due to lopinavir/ritonavir not being specific enough for COVID-19, or that high blood/tissue concentrations are required to inhibit the virus in-vivo.
Chloroquine has been used for more than 70 years, firstly as an anti-malarial drug and later for autoimmune diseases such as rheumatoid arthritis [13]. Additionally, chloroquine has demonstrated antiviral effects by increasing endosomal pH, thus inhibiting endocytosis [13]. Moreover, it inhibits viral replication by interfering with glycosylation of the angiotensin-converting enzyme 2 receptor of SARS-CoV, which the virus uses to enter the patient’s cells [3, 6]. Huang et al. [14] found that COVID-19 patients had higher levels of pro-inflammatory cytokines in their plasma, which might induce a cytokine storm and immunopathological injury [15]. Chloroquine is therefore beneficial in that it can demonstrate immunomodulatory effects, which may reduce complications due to an excessive immune response [16]. In addition, Wang et al. [17] revealed that chloroquine could control SARS-CoV-2 infection in-vitro using a clinically achievable concentration in the plasma, further suggesting that chloroquine may be an effective antiviral therapy during the current outbreak. In our study, we found that chloroquine could reduce the viral load in patients early on, which theoretically should decrease the risk of viral transmission and improve the clinical outcomes of patients. With this being said, 2 patients experienced adverse effects during chloroquine therapy, and concern has previously been raised regarding its toxicity [18]. Therefore, according to the announcements from the National Health Commission of China[9], a patient’s electrocardiogram should be normal before commencing chloroquine therapy, and simultaneous administration of quinolone or macrolide antibiotics should be avoided in these patients. Furthermore, for improved safety, the duration of treatment could be shortened to 7 days, with close attention being paid to the patient for the duration of treatment, especially in patients with a lower weight (<50kg).
As a broad-spectrum antiviral agent, arbidol has demonstrated effectiveness in inhibiting certain respiratory viruses (influenza virus, respiratory syncytial virus, etc.) including SARS-CoV in-vitro [8, 19]. Studies comparing arbidol and lopinavir/ritonavir combination therapy to lopinavir/ritonavir monotherapy in hospitalised, COVID-19 patients, found that the combination therapy group demonstrated an increase in negative SARS-CoV-2 tests by day 7 and day 14 with treatment [20]. Similarly, in our study, the arbidol group showed a decreased shedding interval and an increase in negative SARS-CoV-2 tests at day 10 and at day 14. However, the exact mechanism of arbidol against SARS-CoV-2 has not been determined, thus requiring further study.
Some limitations exist in our study. Firstly, it is a single-centred, small sample size study. Secondly, nucleic acid testing was only performed on upper respiratory tract specimens. Finally, the estimated interval of viral shedding is limited by the frequency of respiratory specimen collection, due to the retrospective study design.
In conclusion, our study revealed that chloroquine and arbidol (Umifenovir) could not only shorten the viral shedding interval, but also decreased the hospitalisation duration and hospitalisation expenses of non-severe, COVID-19 patients. Furthermore, we recommend that large randomised, controlled studies be conducted in the future to better understand the efficacy of various antiviral therapies, dosages and usage durations.