This study investigated the effect of FPV versus LPV/RTV on the treatment of COVID-19. It was found that FPV was
independently associated with faster viral clearance and a higher improvement rate in chest imaging. These findings suggest
that FPV has significantly better treatment effects on COVID-19 in terms of disease progression and viral clearance, as
compared with LPV/RTV. FPV, which is known as a prodrug, is a novel RNA-dependent RNA polymerase (RdRp) inhibitor,
which has been shown to be effective in the treatment of influenza and Ebola virus [8,11–15]. Recently, a report from Wang
et al.  showed that both FPV and remdesivir are effective in reducing the SARS-CoV-2 infection in vitro (EC50 = 61.88
μmol·L−1, CC50 > 400 μmol·L−1, SI > 6.46). The finding of the preset study confirms the hypotheses conceived from the
laboratory finding: that FPV is effective treatment for COVID-19.
The limitation of the present study is that it was not a randomized double-blinded placebo-controlled clinical trial, which
led to inevitable selection bias in patient recruitment. However, given the high number of patients presenting simultaneously
and the very high infectivity of the disease, it was ethically unacceptable to allocate patients to receive a different experimental
drug using a randomization process impossible for most of the patients to understand. Furthermore, in the context of rumors
and distrust of hospital isolation, using a randomized design at the outset might have led even more patients to refuse being
isolated. Therefore, we chose to conduct a nonrandomized trial, in which patients consecutively admitted to the hospital during
two separate periods were included in two groups, respectively. Importantly, all baseline characteristics of the two groups
were comparable and the effectiveness of FPV remained significant after adjustment for potential confounders.
The current study also found that early viral clearance contributed to the improvement of chest imaging on Day 14. This
finding suggests that improvement of the disease may depend on inhibition of the SARS-CoV-2, and that FPV controls the
disease progression of COVID-19 by inhibiting the SARS-CoV-2. Until recently, the pathogenesis of COVID-19 had not
been well clarified. Since the infection of SARS-CoV-2 was thought to be self-limited and characterized by systemic
inflammation reaction, symptomatic and supportive treatment was mainly recommended by the WHO and the National Health
Commission of the PRC. This description is similar to MERS-CoV, for which nonspecific therapeutic interventions are often
introduced to prevent severe morbidity and mortality . How antivirals would contribute to control of the disease is
controversial. Although there have been many registered clinical trials focusing on antiviral drugs for COVID-19, the timing,
duration of treatment, and study endpoints have not been unified. In the current study, the time of viral clearance was
introduced as a primary endpoint to evaluate the antiviral effect of FPV on the SARS-CoV-2 and successfully identify the
priority of FPV. The relationship between the time of viral clearance and the improvement in CT image indicates that viral
clearance is an ideal surrogate for the clinical endpoint. A limitation of the present study was that the relationship between
the viral titer and the clinical prognosis was not well clarified. Future research could pay more attention to this point.
More adverse events were observed in the control arm than in the experimental arm, and were similar to the adverse events
observed in studies of AIDS treated by LPV/RTV. It is worth mentioning that the treatment duration of FPV in the present
study was twice as long as that used for the treatment of influenza. However, the adverse events in the experimental arm were
rare and tolerable, and none of the patients needed to discontinue FPV treatment. These results seem to suggest that the
treatment duration of FPV can be prolonged if necessary.
SARS-CoV-2 infection has now spread quickly all over the world. At present, no effective treatment has been
demonstrated. The task at hand was to run a well-designed trial to identify effective treatments based on a high level of
evidence. However, at the beginning of this study, certain conditions did not allow the randomization of patients to receive
either standard care or an experimental drug. In this pilot study of a non-randomized control trial, we found that FPV showed
significantly better treatment effects on COVID-19 in terms of disease progression and viral clearance; if causal, these results
should be important information for establishing standard treatment guidelines to combat the SARS-CoV-2 infection.
Furthermore, we introduced the time of viral clearance as a primary endpoint for experimental antiviral treatment and
demonstrated it to be a surrogate of clinical endpoint; this will be helpful for designing COVID-19 research.