Adjunctive favipiravir for severe COVID-19: a retrospective observational study of the first 41 patients in Thailand

This study was approved by the Institutional Review Board of Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health (certificate of approval no. S012h_63_ExPD). We used the “Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” cohort checklist when writing our report [8].

In this retrospective observational study, we reviewed all 41 COVID-19 patients confirmed by a positive result on a reverse transcriptase–polymerase chain reaction (RT-PCR) assay of a nasopharyngeal swab specimen. They were admitted at Bamrasnaradura Infectious Diseases Institute (BIDI), Nonthaburi, Thailand, from January 8 to March 30, 2020. One major source of bias is that favipiravir was allowed only for severe COVID-19 cases. Various medication regimens were used based on the dosages summarized in Table 1. Disease severity was classified into three levels: 1 (Mild), 2 (Moderate; abnormal chest X-ray and respiratory rate ≤24 breaths per minute, and 3 (Severe; progressive chest X-ray or respiratory failure). Treatment efficacy was assessed by the time of viral clearance and length of hospital stay.

Descriptive statistics were used to summarize the data; results are reported as means and standard deviations, or medians and interquartile ranges, as appropriate. Categorical variables are presented as counts and percentages. Wilcoxon rank sum test was used to compare the length of stay and days from treatment initiation to negative RT-PCR result. The analysis was performed with Stata/MP 15.1 software (StataCorp LP, College Station, TX, USA).

Forty-one COVID-19 patients were included in this study. Their mean age was 45 years, and 40% were female. Twenty-four patients (58.5%) had no pneumonia (disease severity level 1) whereas three patients (7.3%) were mechanically ventilated and dead (Table 2). Thirteen patients (31.7%) received at least LPV/r or DRV/r, whereas 12 patients (29.3%) also received CQ/HCQ. Ten patients (22.0%) received adjunctive favipiravir, one of whom also received remdesivir.

The median lengths of hospitalization of patients either receiving favipiravir or not receiving favipiravir were not significantly different (P = 0.86), but those who received adjunctive favipiravir became RT-PCR negative 2 days sooner than the other group (median: 6 days vs. 8 days; P = 0.11) (Table 3). No major adverse drug reactions were observed.

Findings from our experience suggest that adjunctive favipiravir might not be effective for patients with severe COVID-19. Given the lack of evidence on the clinical effectiveness of favipiravir on COVID-19 at the initial phase of our study, along with the limited availability of the medications as mentioned earlier, favipiravir was reserved for only severe patients in Thailand. We believe that the clinical outcomes could have been better had favipiravir been administered earlier, as suggested by the potential superior clinical efficacy of adding favipiravir to LPV/r (4).

Initially, we tried to administer favipiravir for only 5 days, which was extended to 10 days based mainly on clinical judgment and partly on the slightly improved chest X-ray findings. This is a good example of the real-life practices that were based mainly on clinical judgment because no standardized treatment protocols were available.

The major limitations of our observational study are as follows: (i) favipiravir was allowed only for severe COVID-19 cases, which is a potential source of bias; and (ii) the relatively small size of the sample, which limited generalization of the findings. This could have been improved by adopting a more robust design, such as a randomized controlled trial with larger sample size. Furthermore, we were not able to collect a comprehensive set of clinical outcomes, such as computed tomography of the chest, quantitative viral assessment, or other blood parameters. However, an early experience of a less-developed country might be beneficial for many other similar contexts.

Adjunctive favipiravir might not be effective for severe COVID-19 patients, but further studies with larger sample sizes are needed.