Drug-induced liver injury by glecaprevir/pibrentasvir treatment for chronic hepatitis C infection: a systematic review and meta-analysis

Figures & data

Figure 1. Flowchart of the identification of eligible trials.

Table 1. Summary and baseline data of patients in included studies [1,3,4,10–14].

Author	Published years	Study name	Study Design	Genotype	Week	Number of patients	SVR12	SVR%	Relapse	Laboratory abnormalities
S. Zeuzem	2018 [2]	ENDURANCE-1,ENDURANCE-3	Two phase 3, randomized, open-label, multicenter trials	1 or 3	8 or 12	1093	1070	97.90	8	ALT, AST, bilirubin
Tarik Asselah	2018 [9]	ENDURANCE-2 ENDURANCE-4 SURVEYOR-II Part 4	Two open label, single-arm studies	2,4-6	8 or 12	526	517	98.29	2	ALT, total bilirubin
Lai Wei	2020 [1]	VOYAGE-1 and VOYAGE-2	Two phase 3 studies	1–6	8 or12	522	511	97.89	7	Platelet count, ALT, AST, total bilirubin
David Wyles	2018 [10]	Part 3 of SURVEYOR-II	A partially-domized, open-label, multicenter, phase 3 study	3	12 or 16	131	125	95.42	3	ALT, total bilirubin
Edward Gane	2019 [3]	SURVEYOR-I and -II; MAGELLAN-1; ENDURANCE-1, −2, −3, and −4; and EXPEDITION-1 and −4)	Nine Phase 2and 3 clinical trials	1–6	8–16	2369	2307	97.38	122	ALT, AST, total bilirubin, platelets
Hidenori Toyoda	2018 [11]	CERTAIN-2 and CERTAIN-1	Two phase 3, open-label, multicenter studies	2	8 or12	108	106	98.15	2	ALT, AST, total bilirubin, haemoglobin
Massimo Puoti	2018 [12]	EXPEDITION-2, EXPEDITION-4, ENDURANCE 1, 2, 3 and 4, SURVEYOR-I Part 2, SURVEYOR–II Parts 1 and 2, and SURVEYOR-II Part 4 studies	Nine phase 2 and 3 trials	1–6	8 or12	2041	2003	98.14	10	ALT, AST, total bilirubin
Steven Flamm	2019 [13]	SURVEYOR-2 Parts 1 and 2 (phase 2), SURVEYOR-2 Part 3 (phase 3), and ENDURANCE-3(phase 3 ) EXPEDITION-2 EXPEDITION-4 MAGELLAN-2	Five clinical trials	3	8,12,16	693	661	95.38	16	ALT, AST, total bilirubin
Kazuaki Chayama	2018 [14]	CERTAIN-1	A phase 3, open-label, multicenter	1	8 or12	167	128	99.22	0	ALT, AST, total bilirubin, haemoglobin
Author	Published years	Race (%)	Gender male, n (%)	Median age (range) year	Median BMI (range)	Baseline fibrosis stage —no. (%)				Previous HCV treatment no. (%)
						F0 or F1	F2	F3	F4
S. Zeuzem	2018 [2]	White (85)	Male (51)	48.8 (20.5–77)	25.3 (17.8-46)	1014 (84)	74 (6)	117 (10)	0	Naïve (76)
Tarik Asselah	2018 [9]	White (68)	Male (53)	53 ± 12.35^§	26.5 ± 5.4^ʃ	513 (81)	47 (7)	66 (11)	0	Naïve (76)
Lai Wei	2020 [1]	Asian (100)	Male (50)	53.25 ± 12.15^§	24.7 ± 3.5^ʃ	282 (54)	24 (5)	55 (11)	156 (30)	Naïve (75)
David Wyles	2018 [10]	White (89)	Male (67)	57.5 (36.75–68.5)	27.5 (20.75–45.75)	26 (20)	6 (5)	12 (9)	87 (66)	Naïve (31)
Edward Gane	2019 [3]	White (80)	Male (56)	328 (14%)^¶	(21%)^λ	1651 (70)	165 (7)	245 (10)	303 (13)	Experienced (31)
Hidenori Toyoda	2018 [11]	Japanese (100)	Female (55)	58 (54%)^¶	22.7 ± 3.7^ʃ	NA	NA	NA	NA	Experienced (20)
Massimo Puoti	2018 [12]	White (79)	Male (55)	52.5(19.5–83.5)	25.4 (17.35–59.9)	1668 (82)	145 (7)	224 (11)	0	Naïve (77)
Steven Flamm	2019 [13]	White (88)	Male (60)	54.2(29.7–70.2)	26.5 (19.3–46)	486 (70)		88 (13)	119 (17)	Naïve (82)
Kazuaki Chayama	2018 [14]	Japanese (100)	Female (62)	94 (56%)^¶	24 ± 4.5^ʃ	NA	NA	NA	NA	Naïve (72)

Notes: Sustained virologic response 12 weeks posttreatment (SVR12) rates (SVR%).

Abbreviations: GT: genotype; G/P”: glecaprevir/pibrentasvir; NA: not available.

Notes: §Age, mean ± SD, years ¶ ≥65 year, no. (%) ʃmean ± SD, kg/m2, λ ≥ 30 kg/m2 no, (%).

Abbreviations: BMI: body mass index; TN: treatment-naïve; TE: treatment-experienced.

Figure 2. Risk of bias of available studies in meta-analysis.

Figure 3. Funnel plot for event rate.

Figure 4. Describes forest plots of Grade 3 adverse events of incidence DILI of glecaprevir plus pibrentasvir. (A) AST, (B) ALT, (C) T-Bil, and (D) Haemoglobin. 95% CI: confidence interval.

Figure 5. Presents forest plots of laboratory abnormalities were evaluated as Grade 2 adverse of glecaprevir plus pibrentasvir. (E) AST, (F) ALT, (G) T-Bil, and (H) haemoglobin. Incidence DILI with 95% CI. CI: confidence interval.

Figure 6. Subgroup analysis in grade 3 hyperbilirubinemia. (I) Without cirrhosis, (J) with cirrhosis (K), treatment for 8 weeks (L), and treatment for >12 weeks.

Figure 7. Subgroup analysis in grade 3 hyperbilirubinemia of HCV infection different genotypes. (GT), (M) GT1, (N) GT2, (O) GT3, and (P) GT1-6.

Table 2. Summary of laboratory abnormalities [1–3,9–14].

Published journals	Author	Published years	Study design	Genotype	Week	Number of patients	Grade 2				Grade 3
							AST 3–5 × ULN	ALT 3–5  × ULN	TB > 1.5–3  × ULN	Haemoglobin (8–10 g/dL)	AST > 5  × ULN	ALT > 5  × ULN	TB > 3–5.0 ×ULN	Platelet count < 50  × 10^9/L
NEJM	S. Zeuzem	2018 [2]	ENDURANCE-1,ENDURANCE-3	1 or 3	8 or 12	1093	1	0	23	0	2	0	4	0
CG&H	Tarik Asselah	2018 [9]	ENDURANCE-2 ENDURANCE-4 SURVEYOR-II Part 4	2,4–6	8 or 12	526	0	0	0	0	0	1	2	0
Lancet	Lai Wei	2020 [1]	VOYAGE-1 and VOYAGE-2	1–6	8 or12	522	0	0	0	0	1	2	1	2
Hepatology	David Wyles	2018 [10]	Part 3 of SURVEYOR-II	3	12 or 16	131	0	0	0	0	0	2	1	0
Clin Infect Dis	Edward Gane	2019 [3]	9 Phase II and III(SURVEYOR-I and -II; MAGELLAN-1; ENDURANCE-1, −2, −3, and −4; and EXPEDITION-1 and −4)	1–6	8–16	2369	0	0	0	0	6	2	12	4
Hepatology	Hidenori Toyoda	2018 [11]	CERTAIN-2 &CERTAIN-1	2	8 or12	108	1	0	6	3	0	0	1	0
J Hepatol	Massimo Puoti	2018 [12]	9 phase 2 and 3 trials	1–6	8 or12	2041	0	0	0	0	7	1	7	0
Jornoal Of Viral Hepatitis (JVH)	Steven Flamm	2019 [13]	SURVEYOR-2 Parts 1 and 2 (phase 2), SURVEYOR-2 Part 3 (phase 3), and ENDURANCE-3(phase 3) EXPEDITION-2 EXPEDITION-4 MAGELLAN-2	3	8,12,16	693	0	4	0	0	2	2	4	0
J Gastroenterol	Kazuaki Chayama	2018 [14]	CERTAIN-1 is a phase 3	1	8 or12	167	1	1	5	3	0	0	0	0

Figure 8. Subgroup analysis in grade 3 events between without cirrhosis and cirrhosis group. (Q and R) ALT (S and T) AST.

Figure 9. Meta-analysis forest plots of glecaprevir/pibrentasvir for chronic HCV infection posttreatment 12 weeks sustained virologic response rates (SVR12).

Figure 10. Subgroup analysis in stratification SVR rate. (U) SVR > 97%, (V) SVR < 97%, and (W) HCV GT3.

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Data availability statement

No data are available in this study.