Effects of Andrographis paniculata and Favipiravir Combination and Monotherapies on Liver Biochemistry in COVID-19 Patients: A Retrospective Cohort Study

Abstract

Introduction and Objective: This study addresses the National Clinical Practice Guideline (CPG) that did not recommend using a combination of favipiravir (FV) and Andrographis paniculata (Burm. f.) Nees (AP, or Fa Thalai Chon in Thai) crude drug (144 mg of andrographolide per day) in the treatment for COVID-19 due to potential serious side effects. The objective is to assess the safety profile of this combination compared to individual
drug use, specifically focusing on liver biochemistry. Additionally, the study aims to identify factors influencing
liver function in patients after FV and/or AP usage.
Methods: The retrospective design involved retrieving medical records of COVID-19 patients who were
admitted to Chao Phya Abhaibhubejhr Hospital between January 1 and December 31, 2021, and who received
either FV, according to the recommended dose by the CPG for 5–10 days thereafter, or AP, with a dose of 4.8 g of
standardized powder (equivalent to 144 mg of andrographolide) per day for 5 days, or a combination of both. The
monitoring was undertaken to identify abnormalities in patients’ liver enzymes, namely aspartate transaminase
(AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin (TB), by identifying deviations
of 2–3 times beyond the upper limit of normal (ULN).
Results: Following the inclusion and exclusion criteria, the records of 564 cases were analyzed. In the assessment
of post-treatment liver enzyme elevation at least 2 times ULN, AP groups (prescribed to younger, healthy
patients) showed no elevations in all four enzymes, and no group displayed increased ALP or TB levels. However,
0.87% in the FV+AP group had AST levels exceeding 3 times ULN, while 1.06% and 2.17% in the FV and FV+AP
groups showed ALT levels over 3 times ULN. One case of drug-induced liver injury (DILI) was observed in both
FV and FV+AP groups. No significant factors increasing abnormal liver enzyme likelihood were identified.
Discussion: Some of the findings could support safety concern regarding the use of combined FV and AP.
However, it should be noted that patients receiving FV and FV+AP may exhibit greater disease severity, so may
those with higher doses of FV medication, underlying diseases, advanced age, and other concurrent medications.
Therefore, it is difficult to conclusively determine whether liver abnormalities are solely attributable to the FV or
FV+AP medication. 

Conclusions and Recommendations: The study indicates that AP at a dose of 144 mg/day showed a
promising safety profile for liver function, suggesting its suitability for young and healthy patients. AP should
also be considered safe for common cold and influenza, with a dosage 3 times lower than that for COVID-19.
However, 1.06% and 2.17% of patients in the FV and FV+AP groups had ALT levels exceeding 3 times, and
0.87% in the FV+AP group had AST levels exceeding 3 times ULN, indicating susceptibility to drug-induced liver
injury (DILI). Therefore, careful monitoring of liver function is warranted following the administration of FV and
FV+AP, especially in older patients, those with underlying diseases, and those taking concomitant medications
metabolized in the liver.