Gastrointestinal and hepatic side effects of potential treatment for COVID-19 and vaccination in patients with chronic liver diseases

Table 1 Gastrointestinal adverse events in key studies investigating treatments for coronavirus disease 2019

Ref.	Dosage	n	Age, yr	Gender, male (%)	Incidence of adverse events in treatment vs control arm, n (%)
					Diarrhea	Vomiting	Abdominal pain	Constipation	Increased AST	Increased ALT	Drug termination due to AE
Lopinavir/ritonavir
Cao et al[31]	400/100 mg twice a day for 14 d	Tx 99; control 100	Median 58 (IQR 49-68)	120 (60.3)	4 (4.2) vs 0	6 (6.3) vs 0	4 (4.2) vs 2 (2.1)	NA	2 (2.1) vs 5 (5.1)	1 (1.1) vs 4 (4.0)	14%
Li et al[32]	200/50 mg, twice a day for 7-14 d	Tx 34; control 17	mean ± SD, 49.4 ± 14.7	40 (46.5)	9/34 (26.5) vs 0	NA	NA	NA	NA	1/21 (4.8) vs 0	1/34 (2.94)
Remdesivir
Beigel et al[50]	200 mg daily on day 1, followed by 100 mg daily on day 2-10	Tx 538; control 521	mean ± SD, 58.9 ± 15.0	684 (64.3)	NA	NA	NA	NA	15 (2.8) vs 20 (3.8)	8 (1.5) vs 9 (1.7)	49 (9.1)
Wang et al[51]	200 mg daily on day 1, followed by 100 mg daily on day 2-10	Tx 158; control 79	Median (IQR) 65 (56-71)	89 (56)	5 (3) vs 2 (3)	4 (3) vs 2 (3%)	NA	21 (14) vs 12 (15)	7 (5) vs 9 (12)	NA	18 (12)
Spinner et al[53]	200 mg daily on day 1, followed by 100 mg daily on day 2-5 or day 2-10	193; 193; 200	Median (IQR) 56 (45-66)	118 (61), 114 (60)	5% vs 6% vs 7%	NA	NA	NA	32 vs 32 vs 33	32 vs 34 vs 39	31 (7.8)
Hydroxychloroquine
Cavalcanti et al[70]	400 mg daily	Tx 221; control 227	mean ± SD, 50.3 ± 14.6	388 (55.3)	NA	0 vs 1 (0.6)	NA	NA	17 (8.5) vs 6 (3.4)	NA	NA
Boulware et al[71]	800 mg once, followed by 600 mg	Tx 414; control 407	Median (IQR) 41 (33-51)	196 (47.3)	81 (23.2) vs 15 (4.3) for diarrhoea or abdominal pain or vomiting	81 (23.2) vs 15 (4.3) for diarrhoea or abdominal pain or vomiting	81 (23.2) vs 15 (4.3) for diarrhoea or abdominal pain or vomiting	NA	NA	NA	17 (4.1)
Favipiravir
Chen et al[80]	1600 mg twice a day on day 1, followed by 600 mg twice daily on day 2-10	Tx 116; control 120	NA	59 (50.86)	NA	NA	NA	NA	10 (8.62)	NA	Nil
Nitazoxanide
Rocco et al[82]	500 mg 3 times per day	Tx 194; control 198	18-77	101 (52)	57 (29.4) vs 49 (24.7)	9 (4.6) vs 3 (1.5)	10 (5.2) vs 5 (2.5)	NA	NA	NA	Nil
Tocilizumab
Stone et al[120]	Tocilizumab 8 mg/kg IV inf not to exceed 800 mg	Tx 161; control 82	Median (IQR) 61.6 (46.4-69.7)	96 (60)	NA	NA	NA	NA	6 (3.7) vs 3 (3.7) for grade 3 or 4	8 (5.0) vs 4 (4.9) for grade 3 or 4	NA

AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; inf: Infusion; IQR: Interquartile range; IV: Intravenous; NA: Not available; Tx: Treatment.

Table 2 Gastrointestinal and hepatic side effects of potential treatments for coronavirus disease 2019

Drug name	Gastrointestinal and hepatic side effects
Remdesivir	Elevation of liver enzymes
Lopinavir-ritonavir	Nausea, vomiting, abdominal pain, gastroenteritis
Hydroxychloroquine/chloroquine	Nausea, vomiting, abdominal pain, diarrhea
Steroids	Epigastric pain, peptic ulcer, risk of HBV reactivation
Interferon	Diarrhea, nausea, elevated alanine aminotransferase level
Ribavirin	Elevated liver enzyme levels
Umifenovir	Nausea, vomiting and deranged liver function
Bromhexine	Deranged liver function
Favipiravir	Diarrhoea, liver enzyme abnormalities
Nitazoxanide	Nausea, vomiting, diarrhoea and abdominal pain
Imervectin	Elevation of liver enzymes
Molnupiravir	Elevated alanine aminotransferase
Tocilizumab	Liver dysfunction
Baricitinib	Nausea, liver dysfunction
Azithromycin	Nausea, vomiting

Table 3 Summary of the ata for the currently used coronavirus disease 2019 vaccines

Vaccine	Mechanism	Number of participants	Efficacy
mRNA-1273 (Moderna)[125]	RNA (embedded in lipid nanoparticles)encodes a variant of the SARS-CoV-2 spike protein	30420 participants (randomized 1:1 vaccine vs placebo)	Efficacy 94.1% (11 vaccinated vs 185 controls with COVID-19)
BNT162b2 (BioNTech and Pfizer)[124]	RNA (embedded in lipid nanoparticles) encodes a variant of the SARS-CoV-2 spike protein	43548 participants (randomized 1:1 vaccine vs placebo)	Efficacy 95% (9 vaccinated vs 169 controls with COVID-19)
ChAdOx1 nCoV-19 (AZD122; AstraZenenca and University of Oxford)[126]	Replication-deficient chimpanzee adenovirus vector, containing the full-length codon-optimized coding sequence of SARS-CoV-2 spike protein	23848 participants (randomized 1:1 vaccine vs placebo)	Efficacy 70.4% [30 (0.5%) of 5807 vaccine recipients vs 101 (1.7%) of 5829 controls with COVID-19]
CoronaVac (Sinovac Life Sciences, Beijing, China)[129,131]	Inactivated vaccine candidate against COVID-19	600 participants	Seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group, and none (0%) of 59 in the placebo group
Sinopharm vaccine[132]	Inactivated vaccine candidate against COVID-19	448 participants	Neutralizing antibodies were detected in 100% of recipients

COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.