Potential Drug Induced Liver Injury (Dili) Event During Remdesivir

Treatment in Covid-19 Patients

Ulvi Nur Rista

1,2

, Desi Setyowati

and Julaeha

Faculty of Pharmacy, Universitas 17 Agustus 1945 Jakarta, Jakarta, Indonesia

Mitra Keluarga Kenjeran Hospital, Surabaya, Indonesia

Keywords: Liver injury, Drug Induced Liver Injury (DILI), Remdesivir, COVID-19, Adverse Drug Reaction.

Abstract: The global pandemic of COVID-19 has already caused about 1.4 million deaths, and liver injury was one of

the foremost problems due to antiviral treatment besides mortality. Remdesivir was one of the antivirals

approved for COVID-19 treatment. Nevertheless, some studies reported that remdesivir caused liver injury.

This study aimed to identify the pattern and severity of liver toxicity during remdesivir treatment. The study

adopted a retrospective cohort design conducted in Mitra Keluarga Kenjeran Hospital Indonesia. This study

involved patients with COVID-19 on remdesivir treatment between June and August 2021. Patients with liver

impairment or abnormal alanine aminotransferase (ALT) were excluded. We described the severity of liver

toxicity based on the grading system and analyzed the comparison of baseline ALT and end-point ALT using

the t-test/Wilcoxon test. The 83 patients were included in this study. Our study showed ALT elevation was

observed in 21 patients (25.3%), including grade 1 in 14 patients (66.7%), grade 2 in 6 patients (28.6%), and

grade 3 in 1 patient (4.7%). Median end-point ALT value was significantly higher than median baseline ALT

(p-value < 0.001). The finding of this study suggests that monitoring of liver function tests must be considered

before the start of remdesivir treatment.

1 INTRODUCTION

Since COVID-19 was declared a global pandemic by

the World Health Organization (WHO) on March 11,

2020, various studies have been conducted to

improve understanding of the characteristics of the

Severe Acute Respiratory Syndrome Coronavirus 2

(SARS-Cov-2). COVID-19 is a disease that

predominantly attacks the respiratory tract, but some

hypotheses suggest that COVID-19 disease can also

attack the kidneys and liver (Sanders et al., 2020).

Some mechanisms that can explain the pathogenesis

of the occurrence of COVID-19-induced liver injury

are direct cytotoxicity of liver cells due to viral

replication, inflammatory responses mediated by the

immune system, responses from hypoxia and

ischemic due to severe sepsis, toxicity from COVID-

19 therapeutic drugs (Aleem et al., 2021).

Drugs used to treat various symptoms are also

increasingly being developed, one of which is

remdesivir. Some research shows that remdesivir has

the potential to cause Drug Induced Liver Injury

(DILI) (Aleem et al., 2021). Remdesivir structurally

belongs to the class of nucleoside drugs.

It is well

known that nucleoside analogues are an important

class of antiviral drugs, which can cause liver

disturbance through a variety of mechanisms. The

most typical mechanism is a mitochondrial type of

liver disturbance, which may be due to the

incorporation of nucleoside analogues into or

blocking mitochondrial DNA synthesis by

mitochondrial gamma polymerase, leading to

mitochondrial depletion (Zhai et al., 2021). This is in

accordance with the cross-sectional study in

Bangladesh in severe COVID-19 patients, the group

who received supportive therapy with remdesivir

showed a significant increase in AST (aspartate

aminotransferase) and ALT (alanine

aminotransferase) compared to the group who

received supportive therapy without remdesivir

(Ghosh et al., 2020). However, in the meta-analysis

study, different results were obtained, the risk of

increasing ALT and AST was significantly lower in

the remdesivir group than placebo/control group

(Angamo et al., 2022). There are differences in the

results of existing studies, so we aimed to conduct a

study to identify the pattern and severity of liver

372

Rista, U., Setyowati, D. and Julaeha, .

Potential Drug Induced Liver Injury (Dili) Event During Remdesivir Treatment in Covid-19 Patients.

DOI: 10.5220/0012025400003582

In Proceedings of the 3rd International Seminar and Call for Paper (ISCP) UTA â

Z45 Jakarta (ISCP UTA’45 Jakarta 2022), pages 372-375

ISBN: 978-989-758-654-5; ISSN: 2828-853X

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

toxicity during remdesivir treatment in COVID-19

patients.

2 METHODS

The study was a cohort retrospective design with

purposively sampled. Ethical approval was obtained

from the Health Research Ethics Committee of 17

August 1945 University, Jakarta with number

30/KEPK-UTA45JKT/EC/EXE/03/ 2022. This study

was conducted at Mitra Keluarga Kenjeran Hospital.

This study involved Inpatients with COVID-19

diagnosed who getting a minimum one dose of

remdesivir in Mitra Keluarga Kenjeran Hospital

between June and August 2021. Patients with liver

impairment or abnormal alanine aminotransferase

(ALT) and getting hepatoprotection treatment

(glycyrrhizin and silymarin) before/during remdesivir

treatment were excluded. All of the patient’s data

were collected from the electronic medical records,

such as patient characteristics, medication treatment

during hospitalized, duration of remdesivir treatment,

baseline and end-point (during/after remdesivir

therapy) ALT value, the clinical manifestation of

COVID-19, co-existing condition, and other COVID-

19 treatment. ALT value was used as a liver injury

marker, because it is more specific for liver damage

than aspartate aminotransferase (AST) (Kim et al.,

2008). Descriptive analysis was performed for patient

characteristics, medication treatment, and percentage

of cases of ALT elevation based on the DILI grading

system developed by the Acquired Immune

Deficiency Syndrome (AIDS) Clinical Trials Group

(CTG). The grading system is used to assess the

severity of liver test abnormality, with the value

expressed as multiples of the upper limit of the

normal range (ULN). The following grades are Grade

1 (1.25-2.5) indicating mild, Grade 2 (> 2.5-5)

moderate, Grade 3 (> 5-10) severe, and Grade 4 (>

10) life-threatening (LiverTox, 2012). Furthermore,

the IBM SPSS for windows version 24.0 was used for

non-parametric analysis. Wilcoxon signed-rank test

was performed to find out differences in ALT value

between baseline and end-point measurement, p-

value < 0.05 means statistical significantly.

3 RESULTS AND DISCUSSION

3.1 Results

In total, 159 patients received remdesivir treatment

from June until August 2021. 76 of these patients

were excluded because of missing end-point ALT, the

elevation of ALT on pre-remdesivir, getting

hepatoprotection treatment before/after the start of

remdesivir, and getting double antivirals. Of the 83

remaining patients included in this study.

3.1.1 Baseline Characteristics of Patients

Table 1 shows the demographic and clinical

characteristics of 83 patients in this study. A total of

43 patients (52%) were women, the mean age was 56

± 16.35 years. The mean duration of remdesivir

treatment was 6.5 ± 1.95 days. Most patients (58

patients (69.9%)) had moderate symptoms on

admission. Of 3 patients (3.6%) had mild symptoms

on admission, but they got remdesivir because of

worsening symptoms during the in-hospital. The

most of patients having co-existing conditions were

hypertension (33 patients (39.8%)) and type 2

diabetes mellitus (25 patients (30.1%). More than

50% of patients got other drugs, which are

levofloxacin and dexamethasone.

Table 1: Demographic and Clinical Characteristics of the

Patients (N=83).

Patient characteristic N

(

)

Sex

Men 40

(

48%

)

Women 43(52%)

Age (years)

56 ± 16.35

Clinical manifestation of COVID-19

Mil

3.6%

Moderate 69.9%

Severe 26.5%

Co-existin

condition

ertension 39.8%

Type 2 Diabetes

Mellitus

30.1%

Chronic Kidne

Disease 4.8%

Coronary Heart Disease 9.6%

Dyslipidemia 6.0%

Stroke 1.2%

Asthma 2.4%

Duration of remdesivir

treatment (days)

6.5 ± 1.95

Othe

medication*

Levofloxacin 68.67%

Azithrom

cin 4.82%

Moxifloxacin 12.05%

Dexamethasone 57.83%

Hydrocortisone 3.61%

Tocilizumab 26.51%

*Other medication belongs to standard of care of COVID-

19 in Indonesia

Potential Drug Induced Liver Injury (Dili) Event During Remdesivir Treatment in Covid-19 Patients

373

3.1.2 An ALT Elevation during Remdesivir

Treatment

Based on classification of DILI by AIDS CTG, ALT

elevation was observed in 21 patients (25.3%),

including grade 1 elevation in 14 patients, grade 2

elevation in 6 patients, and grade 3 in 1 patient. The

majority of patients who having ALT elevation were

men, having moderate symptoms and the mean

duration of remdesivir treatment was approximately

5-9 days (shown in Table 2)

Table 2: The Characteristic of Patients Who Having ALT

Elevation (N=21).

Characteristics Grade 1

(

N=14

)

Grade 2

(

N=6

)

Grade 3

(

N=1

)

Age (years)

44.8 ± 10.8 43 ± 20

Sex

Men 7 4 1

Women 7 2 0

Clinical Manifestation of COVID-19

Mil

1 1 0

Moderate 8 3 0

Severe 5 2 1

Duration of

Remdesivir

Treatment

(days)

6.9 ± 1.8 6.5 ± 2.0

Table 3: Statistic Result of The Difference in ALT Level.

ALT level Median

(interquartile

ran

)

p value*

Baseline 22 (14) < 0.001

oint 29 (33)

*Wilcoxon test, the ALT level decreased in 29 patients,

increased in 49 patients, and steady in 5 patients

Table 3 showed there was significantly

differences (p<0.001) ALT value before and

during/after (end-point) remdesivir treatment. There

are several drugs of standard therapy in COVID-19

other than remdesivir, were used in this study, which

may be caused liver toxicity according to the

likelihood score of DILI LiverTox. These drugs have

shown in Table 4, including the percentage of patients

who received concomitant medications.

Table 4: Percentage of Patients with Concomitant

Medications (N=83).

Medication ALT

elevation

Grou

(

N=21

)

ALT non-

elevation

Grou

(

N=62

)

Levofloxacin 15

(

71.43%

)

(

67.74%

)

Azithromycin 2 (9.52%) 2 (3.23%)

Moxifloxacin 2

(

9.52%

)

(

1.9%

)

Dexamethasone 20 (95.2%) 28 (45.16%)

Hydrocortisone 1 (4.76%) 2 (3.23%)

Tocilizumab 8

(

38.10%

)

(

22.58%

)

3.2 Discussion

Liver injury associated COVID-19 has occurred in

14-53% of patients. Various mechanisms have been

hypothesized to explain that pathogenesis, such as the

the worsening of COVID-19 illness and drug toxicity.

Several drugs in the management of COVID-19 are

potential hepatotoxic (Aleem et al., 2021). Liver

injury during remdesivir treatment was reported and

registered in WHO vigibase pharmacovigilance.

Increased liver transaminase (88%) was the most

frequent adverse drug reaction of remdesivir

(Montastruc et al., 2020). These reports are consistent

with our result that ALT value increased significantly

during/after remdesivir treatment (p<0.001).

According to the AIDS CTG grading system, ALT

elevation occurred in 21 patients (25.3%). Our result

is contrary to a meta-analysis study which showed

that treatment with remdesivir was associated with a

lower risk of ALT elevation (p=0.006) (Angamo et

al., 2022). However, the cut-off value of ALT to

define ALT elevation in that study was unclear.

We also found that most of our patients had mild-

moderate liver injury (grade 1-2), and only one had a

severe liver injury (grade 3). All of our patients didn’t

require to stop remdesivir, some patients got

hepatoprotection treatment. This finding was also

reported by Ghosh, et al, that remdesivir caused

frequent grade-1 (1.25 to 3-fold) and grade-2 (3 to 5-

fold) elevation of ALT which didn’t require drug

discontinuation (Ghosh et al., 2020). In contrast to

Wang et al., two patients with severe COVID-19 in

the remdesivir group had increased ALT events (any

grade) leading to drug discontinuation (Wang et al.,

2020).

We observed liver injury in our study possibly

occurred in patients with moderate COVID-19

illness. In most of the previous studies, liver injury

following remdesivir treatment occurred in patients

with severe-critical COVID-19 illness, due to

subjects who included in that studies were only

severe/critical illness (Ghosh et al., 2020; Grein et al.,

2020; Wang et al., 2020).

According to the standard of therapy in the

national guideline, our patients got other drugs than

remdesivir such as dexamethasone, levofloxacin, and

tocilizumab. All three were the most used

concomitant with remdesivir. Based on the likelihood

score of DILI LiverTox, dexamethasone and

ISCP UTA’45 Jakarta 2022 - International Seminar and Call for Paper Universitas 17 Agustus 1945 Jakarta

374

levofloxacin are well-established causes of liver

injury (Category A), and tocilizumab is a probable

rare cause of liver injury (Category C) (LiverTox,

2012). Therefore, the possibility of another cause-

induced liver injury could not be sorted.

A caution interpretation of the findings of this

study is required due to several methodological

limitations. Firstly, the sample size of the study might

not reflect and represent overall liver injury condition

due to remdesivir in Indonesia. Further study with

multiple sites and large sample size is necessary.

Secondly, this study did not observe a long-term

period of the patient’s clinical condition. Therefore, a

longitudinal study is strongly recommended to

observe the effect of remdesivir on liver injury.

Despite several limitations, our study has superiority

in milestone contribution on evidence-based

providing of remdesivir safety and efficacy in

COVID-19 treatment.

4 CONCLUSIONS

This study highlighted that ALT elevation is probably

due to remdesivir. Mostly, this event occurred in

moderate COVID-19 patients. However, there were

other causes of induced liver injury that could not be

sorted.

ACKNOWLEDGEMENTS

The authors appreciated Mirta Keluarga Kenjeran

Hospital, Surabaya to support this study by providing

and facilitating data collection.

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