Abstract
We report the clinical outcomes following implementation of initial
COVID-19 treatment guidelines in Thailand. A composite poor outcome was
defined as death, ICU admission, requiring intubation, or high-flow
oxygen. 744 COVID-19 patients (48.8% male) were included, median (IQR)
age was 37 (27-48) years [8.4% >60 years] and 21.4%
had pneumonia at admission. Admission < 4 days from
symptom onset had a reduced risk of poor outcome. In a subgroup
analysis, favipiravir use reduced the risk of a poor outcome for
patients admitted < 4 days from symptom onset (OR 0.320
(0.152-0.662), P=0.003). Thai guidelines now include favipiravir to
treat all symptomatic COVID-19 patients.
Keywords : COVID-19, Favipiravir, Thailand
Main text: Thailand is one of the few countries that has been
able to successfully control the COVID-19 outbreak. As of January 10,
2021, there were 10,294 confirmed cases of COVID-19 in Thailand,
resulting in 69 deaths. Thailand encountered its first outbreak in early
March 2020 originating from attendees of a famous Thai Boxing
competition in Bangkok which rapidly spread to individuals in
surrounding bars and night clubs resulting in more than 2,500 cases. Due
to this rapid surge in cases, the Ministry of Public Health held
meetings with multidisciplinary experts, including infectious diseases
specialists, pulmonologists, intensivists, and policymakers, to develop
clinical practice guidelines to guide clinicians using the scientific
evidence available at that time. The first version of the COVID-19
guidelines was posted on March 21, 2020 and recommended (i) No antiviral
treatment for asymptomatic patients and (ii) Combination antiviral
treatment directed against different viral targets for symptomatic
cases, with the regimen dependent on the presence or absence of
pneumonia COVID-19 illness. For patients with non-pneumonia COVID-19
illness but with specific risk factors, e.g. age >60 years
or <5 years, BMI>35 kg/m2,
immunocompromised, diabetes, chronic conditions of lungs, kidney, liver,
cardiovascular or cerebrovascular diseases, or lymphocytes
<1,000 cells/mm3, the recommended treatment
was chloroquine (CQ) (500 mg, twice daily) or hydroxychloroquine (HCQ)
(600 mg, twice daily on the first day, then 400 mg twice daily) plus a
boosted protease inhibitor (bPI) (lopinavir/ritonavir 400/100 mg, twice
daily or darunavir/ritonavir 600/100 mg, twice daily). A triple drug
combination of CQ or HCQ, a bPI, and favipiravir (FPV), an oral RNA
dependent RNA polymerase inhibitor (60 mg/kg/day twice daily on the
first day, then 20 mg/kg/day twice daily afterwards) was recommend for
patients with pneumonia COVID-19 illness. The use of FPV for only the
most severe cases was due to the limited availability at that time. The
duration of treatment was 5 days but could be extend to 10 days in cases
of severe pneumonia. Azithromycin was recommended as adjunctive
treatment for all symptomatic cases, particularly for severely ill
patients. All COVID-19 patients were hospitalized regardless of
symptoms. Our aim was to describe the clinical outcomes following
antiviral treatment according to these initial guidelines and identify
factors associated with a poor clinical outcome.
Nine large hospitals in Bangkok were invited to submit data on their
COVID-19 patients using standardized case record forms. Data collected
from March to June, 2020, included demographics, initial diagnosis,
antiviral and antibiotic treatment, clinical outcome, including the need
for oxygen therapy (intubated, high-flow, or lower oxygen support),
intensive care unit (ICU) admission, and death. A composite poor outcome
was defined as death, ICU admission, requiring intubation, or requiring
high-flow oxygen. If treatment was indicated, antiviral treatment was
initiated on the day of admission; however, favipiravir initiation may
be delayed for a day in some hospitals due to approval and drug delivery
process. Factors associated with the composite poor outcome were
assessed using multivariate analysis. The study was approved by the
local Ethics Committee.
A total of 744 COVID-19 patients (48.8% male) were included in this
analysis with a median (interquartile range) age of 37 (27-48) years
[8.4% >60 years], 5.6% were obese and 16.5% had
underlying conditions. At hospital admission, 28.4% were asymptomatic,
50.2% had non-pneumonia illnesses, of which 22.7% had risk factors,
and 21.4% had pneumonia (Figure 1). 637 (85.6%) cases received
antiviral treatment in compliance with the guidelines. Overall, there
were 8 (1.1%) deaths, 66 (8.9%) required ICU admission, 17 (2.3%)
required intubation, and 19 (2.6%) required high-flow oxygen. Seventy
(9.4%) of patients had at least one of these outcomes (composite poor
outcomes).
In univariate analysis among symptomatic patients, factors associated
with a higher risk of a composite poor outcome were: being male (odd
ration [OR] 1.89 (95% confidential interval [CI] 1.12-3.20),
P=0.018), >60 years-old (OR 4.42 (2.36-8.27),
P<0.001), obesity (OR 2.79 (1.32-5.88), P=0.007) , underlying
risk condition (OR 4.14 (2.45-6.99), P<0.001), pneumonia at
admission (OR 11.51 (6.32-20.94), P<0.001), receiving an
initial regimen containing FPV (OR 10.65 (5.62-20.17),
P<0.001) and azithromycin use (OR 4.52 (2.68-7.62),
P<0.001). Admission to the hospital within 4 days from symptom
onset significantly reduced the risk of a composite poor outcome (OR
0.30 (0.17-0.52), P<0.001), and this remained significant
among patients with pneumonia at presentation (OR 0.34 (0.16-0.72),
P=0.005), but not among patients with non-pneumonia illness (OR 0.65
(0.24-1.77), P=0.397). The longer time to hospital admission
significantly increased the risk of poor outcome (OR 1.10 (1.04-1.16),
P=0.001), i.e. the risk of a composite poor outcome increased 10% each
day from symptom onset until hospital admission.
In a multivariate analysis of symptomatic patients, factors associated
with a composite poor outcome were an underlying risk conditions,
receiving an initial regimen containing FPV, and azithromycin use; while
admission within 4 days of onset of symptoms was associated with a
reduced risk of a poor composite outcome (Table 1).
A triple drug antiviral regimen of CQ/HCQ + bPI + FPV was associated
with a composite poor outcome but this was likely due to its use only in
the sickest patients. However, in a subgroup analysis, regimens with FPV
reduced the risk of a poor outcome for patients admitted< 4 days from symptom onset, compare to after 4 days,
even after adjusting for confounding factors (OR 0.320 (0.152-0.662),
P=0.003) (Table 2). This benefit was not observed for patients receiving
regimens using CQ/HCQ plus bPI without FPV.
Large studies have reported no benefit of lopinavir1,2and hydroxychloroquine3-5and we also observed no clear
benefit of this dual treatment combination. Recent data from the
open-label randomized SOLIDARITY study,6 led by WHO,
found that neither remdesivir, hydroxychloroquine, lopinavir, nor
interferon beta-1a treatment reduce overall mortality. No benefit of
remdesivir in terms of all-cause mortality was also reported in the
ACTT-1 trial,7 but remdesivir did significantly
decrease the time to recovery (10 vs 15 days, RR 1·29, 95% CI
1·12–1·49), with a clear benefit for patients starting treatment within
10 days of symptom onset. The approval of remdesivir for COVID-19
treatment is encouraging but widespread access is expected to be limited
in most resource-limited settings, including Thailand. Favipiravir has a
similar antiviral mechanism to remdesivir and can easily be scaled up in
Asia due to its lower cost and simpler oral administration. Studies have
shown favipiravir to be effective in viral clearance and improve
clinical outcomes when compared to
lopinavir/ritonavir8 or with
arbidol9, or without antiviral
treatment.10 Initiation of FPV ‘early’ compared to
‘late’ (6 days later) was found to reduce the time to defervescence in
Japanese adults admitted with COVID-19 who were asymptomatic or mildly
ill. Data from our study, while observational, indicates that early
treatment (<4 days from symptom onset) with a combination of
antivirals containing favipiravir reduces the risk of a poor outcome.
These data build on the evidence that early antiviral treatment could be
beneficial while later antiviral treatment after the process of
hyperinflammatory has kicked in, and viral load11waning, is less effective, and instead a glucocorticoid would help
reduced mortality.12
The initial Thai guidelines were based on available data at that time
with many of the evidence based on in-vitro data. Considering the
recent literature, along with these local data, Thai guidelines were
recently revised to stop using CQ/HCQ plus bPI, and recommend using
favipiravir early in the course of illness for symptomatic patients
independent of risk factors. It is conceivable that early treatment with
FPV per initial guidelines could have contributed towards the relatively
low mortality observed in our setting. In the second wave in Thailand,
favipiravir plays an important role for the treatment of COVID-19.