During the study period, there were a total of 274 COVID-19 patients hospitalized in the
participating hospitals, of which 63 patients (23.0%) had evidence of pulmonary involvements. All of them received favipiravir therapy according to the Thai national clinical practice guidelines. The total of 63 patients were enrolled into the study. The baseline demographics and characteristics of all patients are listed in Table 1.
The median age of patients was 48 (22–85) years, and 39 of these patients (61.9%) were male. Most patients had fever (87.3%), sore throat (69.8%), or cough (74.6%) as the clinical presentation. The median duration between the symptom onset and the admission date was 6 (0–28) days, while the median duration between the symptom onset and the first day of favipiravir therapy was 8 (0–28) days.
At baseline (Day 1 of favipiravir therapy), 17 patients (27.0%) required O2-supplementation via nasal cannula, 6 patients (9.5%) required non-invasive ventilation and/or high-flow O2-therapy, and 4 patients (6.4%) required invasive mechanical ventilation and/or ECMO, while the remainder did not required O2-supplementation. The median baseline NEWS2 score was 5 (0–16).
The median loading dose of favipiravir was 47.4 (29.1–71.1) MKD, and one-third of enrolled patients (33.3%) received a loading dose of ≤45 MKD. The median maintenance dose of favipiravir was 17.9 (10.9–26.7) MKD, and 76.2% of the subjects received a maintenance dose of ≤15 MKD. The median duration of favipiravir therapy was 12 (2–17) days. Within two days of initiating favipiravir treatment, nearly all patients were prescribed a chloroquine-based agent (98.4%) and a protease inhibitor (96.8%); half of them also received azithromycin (49.2%). Only a few patients received a steroid (12.7%) or tocilizumab (6.4%) at this time.
Hospital course and treatment outcomes
Details regarding the hospital course and treatment outcomes are shown in Table 2. The Day-7, Day-14, and Day-28 clinical improvement rates, stratified by the requirement for O2-supplementation are depicted in Figure 1. The Day-7 clinical improvement rate [95%CI] was 66.7% [53.7–78.0%] in all patients, 92.5%[75.7–99.1%] in patients who did not require O2-supplementation (a six-point disease severity scale score of 1–2), and 47.2% [0.4–64.5%] in patients who required O2-supplementation (a six-point severity scale score of 3–5). The Day-14 clinical improvement rates for all patients, those who did not require O2-supplementation, and those who required O2-supplementation were 85.7% [74.6%–93.2%], 100.0% [87.2%–1.00%], and 75.0% [57.8%–87.9%], respectively. Nearly all patients who required O2-supplementation (96.1%) had clinical improvement within 28 days.
Of these 63 study patients, four patients required invasive mechanical ventilation or ECMO on Day 1 of therapy, and four more cases subsequently required invasive mechanical ventilation (two cases on Day 6 and two cases on Day 9 of therapy). The 14-day, 28-day, and in-hospital mortality rates were 1.6%, 4.8%, and 7.9%, respectively. The major cause of death was superimposed infection.
The most common adverse event was diarrhea (54.0%), follow by nausea/vomit (7.9%), hepatitis (6.4%), and QT interval prolongation in EKG (6.4%). None of these adverse events were life-threatening.
Factors associated with Day-7 clinical improvement
To determine the factors associated with Day-7 clinical improvement, we compared patients
with Day-7 clinical improvement (cases) with patients without Day-7 clinical improvement (controls). The characteristics of both groups are shown Table 1. The cases had a significantly lower age (47 vs. 59 years; p = 0.02), a significantly lower BMI (25.0 vs. 27.9; p = 0.04), a significantly lower baseline NEWS2 score (4 vs. 5; p = 0.003), and a significantly lower baseline six-point disease severity scale score (2 vs. 3; p < 0.001). Additionally, the baseline white blood cell count was significantly lower in the case group (5420 vs. 6810; p = 0.03). Although the median loading and maintenance doses of favipiravir were not statistically different between these groups, the proportion of patients in the control group who received a lower loading dose of favipiravir (≤45 MKD) trended higher compared with the case group (26.2% vs. 47.6%; p < 0.10).
Table 3 shows the results of multivariate analysis. A multivariate analysis revealed three factors that were negatively associated with Day-7 clinical improvement [odds ratio (95%CI); p-value]: older age [0.94 (0.89–0.99); p = 0.04], higher baseline NEWS2 score [0.64 (0.47–0.88); p = 0.006], and a lower prescribed loading dose of favipiravir (≤45 MKD) [0.04 (0.005–0.4); p = 0.006].