Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Oliveira-Silva, Nayara Aparecida de; Figueras, Albert; Melo, Daniela Oliveira de

doi:10.1590/s2175-97902023e21471

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 59 • 2023 • https://doi.org/10.1590/s2175-97902023e21471 copy

Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

Keywords:
COVID-19; Hepatotoxicity; Pharmacovigilance; Drug-drug interaction

	Remdesivir				Tocilizumab				Lopinavir-Ritonavir				Hydroxychloroquine
	Liver events		Non-liver events		Liver events		Non-liver events		Liver events		Non-liver events		Liver events		Non-liver events
	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%
Reports COVID-19	34	100.0	1142	100.0	168	100.0	494	100.0	298	100.0	446	100.0	426	100.0	955	100.0
Sex
Women	13	38.2	439	38.4	53	31.5	94	19	80	26.8	113	25.3	128	30	214	22.4
Men	20	58.8	696	60.9	105	62.5	270	54.7	206	69.1	279	62.6	272	63.8	482	50.5
N/A	1	2.9	7	0.6	10	6	130	26.3	12	4	54	12.1	26	6.1	259	27.1
Age (years)
< 18	0	0	8	0.7	1	0.6	0	0	0	0	5	1.1	1	0.2	5	0.5
18 - 64	17	50	591	51.8	127	75.6	208	42.1	173	58.1	175	39.2	285	66.9	299	31.3
65 - 79	13	38.2	399	34.9	28	16.7	128	25.9	90	30.2	176	39.5	86	20.2	278	29.1
> 80	3	8.8	125	10.9	1	0.6	18	3.6	23	7.7	41	9.2	26	6.1	97	10.2
N/A	1	2.9	19	1.7	11	6.5	140	28.3	12	4	49	11	28	6.6	276	28.9
Suspected concomitant drug
Hydroxychloroquine	0	0	0	0	130	77.4	61	12.3	104	34.9	193	43.3	173	40.6	669	70.1
Lopinavir-Ritonavir	0	0	0	0	7	4.2	4	0.8	168	56.4	218	48.9	104	24.4	193	20.2
Remdesivir	34	100	1135	99.4	0	0	6	1.2	0	0	0	0	0	0	0	0
Tocilizumab	0	0	6	0.5	12	7.1	391	79.1	7	2.3	4	0.9	130	30.5	61	6.4
Tocilizumab and hydroxychloroquine	0	0	1	0.1	-	-	-	-	19	6.4	31	7	-	-	-	-
Tocilizumab and lopinavir-ritonavir	0	0	0	0	-	-	-	-	-	-	-	-	19	4.5	31	3.2
Hydroxychloroquine and lopinavir-ritonavir	0	0	0	0	19	11.3	31	6.3	-	-	-	-	-	-	-	-
Hydroxychloroquine and remdesivir	-	-	-	-	0	0	1	0.2	0	0	0	0	-	-	-	-
Remdesivir and tocilizumab	-	-	-	-	-	-	-	-	0	0	0	0	0	0	1	0.1

Drug	Adverse drug reactions	Reports
		COVID-19	Other uses or unknown use	ROR
		n (%)	n (%)	ROR
Tocilizumab	ALT Increased	18 (2.72)	439 (0.93)	2.99 (1.85 - 4.82)
	AST Increased	13 (1.96)	367 (0.77)	2.57 (1.47 - 4.49)
	Hepatitis	124 (18.73)	324 (0.68)	33.37 (26.76 - 47.86)
	All liver events	168 (25.38)	2420 (5.11)	6.32 (5.28 - 7.56)
	Total notifications	662 (100.00)	47374 (100.00)	Not applicable
Remdesivir	ALT Increased	164 (13.95)	15 (12.71)	Not applicable^a
	AST Increased	130 (11.05)	12 (10.17)	Not applicable^a
	Hepatitis	1 (0.085)	0 (0.00)	Not applicable^a
	All liver events	34 (2.89)	2 (1.69)	Not applicable^a
	Total	1176 (100.00)	118 (100.00)	Not applicable^a
Lopinavir/ritonavir	ALT Increased	9 (1.21)	207 (1.82)	0.66 (0.34 - 1.29)
	AST Increased	20 (2.69)	201 (1.77)	1.54 (0.96 - 2.45)
	Hepatitis	31 (4.17)	147 (1.29)	3.32 (2.24 - 4.93)
	All liver events	298 (40.05)	1121 (9.85)	6.12 (5.22 - 7.17)
	Total	744 (100.00)	11383 (100.00)	Not applicable
Hydroxychloroquine	ALT Increased	13 (0.94)	322 (1.03)	0.91 (0.32 - 1.59)
	AST Increased	5 (0.36)	266 (0.85)	0.51 (0.23 - 1.14)
	Hepatitis	220 (15.93)	228 (0.73)	25.71 (21.17 - 31.22)
	All liver events	426 (30.85)	1460 (4.69)	9.07 (8 - 10.29)
	Total	1381 (100.00)	31161 (100.00)	Not applicable

Drug	All adverse liver events ROR (CI 95%)	Hepatitis ROR (CI 95%)	ALT Increased ROR (CI 95%)	AST Increased ROR (CI 95%)
Hydroxychloroquine vs L/r, tocilizumab and remdesivir	3.54 (2.96 - 4.24)	31.00 (17.26 - 55.67)	0.10 (0.05 - 0,17)	0.04 (0.02 - 0.10)
L/r vs hydroxychloroquine, tocilizumab and remdesivir	4.33 (3.60 - 5.21)	0.36 (0.25 - 0.53)	0.16 (0.08 - 0.32)	0.47 (0.29 - 0.76)
Tocilizumab vs hydroxychloroquine, L/r, and remdesivir	1.57 (1.29 - 1.92)	5.52 (4.20 - 7.26)	0.41 (0.25 - 0.67)	0.33 (0.19 - 0.59)
Remdesivir vs hydroxychloroquine, L/r, and tocilizumab	0.08 (0.05 - 0.11)	Not applicable^a	13.43 (8.82 - 20.44)	7.62 (5.21 - 11.14)
Tocilizumab vs Remdesivir
Tocilizumab (all) vs Remdesivir	11.35 (7.74 - 16.66) ^b	Not applicable^a	0.17 (0.11 - 0.29)	0.16 (0.09 - 0.29)
Tocilizumab (alone) vs Remdesivir	1.02 (0.53 - 2.00)	Not applicable^b	0.23 (0.12 - 0.43)	0.22 (0.13 - 0.39)
Tocilizumab + Hydroxychloroquine
Tocilizumab + Hydroxychloroquine vs Remdesivir	53.85 (34.85 - 82,08)	Not applicable^a	0.08 (0.02 - 0.25)	0.03 (0.00 - 0.24)
Tocilizumab + Hydroxychloroquine vs Tocilizumab alone or associated with L/r and/or remdesivir	33.81 (19.94 - 57.34)	80.30 (32.09 - 200.92)	0.34 (0.10 - 1.18)	0.14 (0.02 - 1.09

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: D. O. de Melo. Universidade Federal de São Paulo (UNIFESP). Avenida Conceição, 329, Centro. CEP: 09920-000, Diadema, SP, Brasil. E-mail: melo.daniela@unifesp.br.