The impact of sofosbuvir/velpatasvir/voxilaprevir treatment on serum hyperglycemia in hepatitis C virus infections: 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.

Author	Published years	Study design	Study name	HCV genotype, n (%)		Intervention	Week	Median age (range) years	Gender Male, n (%)	Race White, n (%)
Bourlière et al. [3]	2017	An open-label phase 3 trial study	POLARIS-1	GT1–6	GT1 150 (99)	Matched placebo	12	59 (29–80)	121 (80)	124 (82)
					GT1 150 (57)	SOF-VEL-VOX	12	58 (27–84)	200 (76)	211 (80)
			POLARIS-4	GT1–6	GT1 78 (43)	SOF-VEL-VOX	12	57 (24–85)	143 (79)	160 (88)
					GT1 66 (44)	SOF-VEL	12	57 (24–80)	114 (75)	131 (87)
Lawitz et al. [31]	2017	A phase 2, open-label study	–	GT1	GT1 (100)	SOF-VEL-VOX	12	54 (18–71)	16 (67)	17 (71)
					GT1 (100)	SOF-VEL-VOX + RBV	12	54 (22–75)	16 (64)	22 (88)
Jacobson et al. [24]	2017	In two phase 3, open-label trials	POLARIS-2	GT1–6	GT1 233(47)	SOF-VEL-VOX	8	53 (18–78)	255 (51)	391 (78)
					GT1 232(53)	SOF-VEL	12	55 (19–82)	237 (54)	365 (83)
			POLARIS-3		GT3 110 (100)	SOF-VEL-VOX	8	54 (25–75)	74 (67)	100 (91)
					GT3 109 (100)	SOF-VEL	12	55 (31–69)	100 (92)	97 (89)
Gane et al. [30]	2016	An open-label study	–	GT1, 3	GT1a 11 (73)	SOF-VEL-VOX	4	54 (40, 64)	9 (60)	12 (80)
					GT1a 11 (73)	SOF-VEL-VOX	6	50 (24, 65)	7 (47)	14 (93)
					GT1a 14 (93)	SOF-VEL-VOX	6	59 (51, 66)	11 (73)	14 (93)
					GT1a 23 (77)	SOF-VEL-VOX	6	55 (35, 73)	24 (80)	27 (90)
					GT1a 15 (88)	SOF-VEL-VOX	8	58 (48, 70)	14 (82)	16 (94)
					GT1a 24 (86)	SOF-VEL-VOX	8	57 (39, 66)	19 (68)	24 (86)
					GT3 18 (100)	SOF-VEL-VOX	6	52 (39, 64)	10 (56)	12 (67)
					GT3 19 (100)	SOF-VEL-VOX	8	55 (44, 66)	15 (79)	18 (95)
					GT3 4 (100)	SOF-VEL-VOX	8	56 (43, 62)	4 (100)	3 (75)
Lawitz et al. [29]	2016	An open-label, two-cohort, phase 2 study	–	GT1	GT1a 27 (79)	SOF-VEL-VOX	6	53	23 (68)	31 (91)
					GT1a 28 (78)	SOF-VEL-VOX	8	51	21 (58)	32 (89)
					GT1a 26 (79)	SOF-VEL-VOX	8	58	19 (58)	25 (76)
					GT1a 25 (81)	SOF-VEL-VOX + RBV	8	59	19 (61)	26 (84)
					GT1a 27 (87)	SOF-VEL-VOX	12	57	23 (74)	27 (87)
					GT1a 24 (75)	SOF-VEL-VOX	12	59	26 (81)	26 (81)
Author	Published years	Intervention	Week	Patients	Cirrhosis, no. (%)	Mean HCV RNA SD (log10 IU/ml)	Prior DAAs by class, n (%)					Relapse, n (%)	SVR12, % (95% CI)	Grade 3 Hyperglycemia^§, n (%)
							NS5A + NS3  ± NS5B	NS5B  ± NS3	NS5A ± NS5B	Treatment -naïve	Others
Bourlière et al. [3]	2017	matched placebo	12	152	51 (34)	6.3 ± 0.6	62 (41)	1 (1)	80 (53)	–	–	–	–	7 (4.61)
		SOF-VEL-VOX	12	263	121 (46)	6.3 ± 0.7	83 (32)	0	161 (61)	–	–	6/261 (2)	96 (93.6–98.4)	5 (1.90)
		SOF-VEL-VOX	12	182	84 (46)	6.3 ± 0.6	0	46 (25)	0	–	–	1/182 (1)	98 (96–100)	4 (2.20)
		SOF-VEL	12	151	69 (46)	6.3 ± 0.7	0	38 (25)	0	–	–	14/150 (9)	90 (85–95)	3 (1.99)
Lawitz et al. [31]	2017	SOF-VEL-VOX	12	24	11 (46)	6.2 6 ± 0.42	6 (25)	14 (58)	4(16)	–	–	0	100 (86–100)	0 (0)
		SOF-VEL-VOX + RBV	12	25	14 (56)	6.3 6 ± 0.46	4 (16)	15 (60)	6 (24)	–	–	1 (4)	96 (80–100)	1 (4.00)
Jacobson et al. [24]	2017	SOF-VEL-VOX	8	501	90 (18)	6.1 (0.75)	501	–	–	383 (76)	–	21 (4)	95 (93–97)	7 (1.40)
		SOF-VEL	12	440	84 (19)	6.2 (0.66)	440	–	–	340 (77)	–	3 (1)	98 (97–99)	3 (0.68)
		SOF-VEL-VOX	8	110	110 (100)	6.0 (0.80)	110	–	–	75 (68)	–	2 (2)	96 (92–100)	8 (7.27)
		SOF-VEL	12	109	109 (100)	6.3 (0.63)	109	–	–	77 (71)	–	1 (1)	96 (92–100)	3 (2.75)
Gane et al. [30]	2016	SOF-VEL-VOX	4	15	0	6.3 (0.5)	–	–	–	15 (100)	–	11 (73)	27 (8–55)	0 (0)
		SOF-VEL-VOX	6	15	0	6.0 (0.7)	–	–	–	15 (100)	–	1 (7)	93 (68–100)	0 (0)
		SOF-VEL-VOX	6	15	15 (100)	6.0 (0.9)	–	–	–	15 (100)	–	2 (13)	87 (60–98)	1 (6.67)
		SOF-VEL-VOX	6	30	5 (17)	6.3 (0.5)	–	–	–	–	DAA	10 (30)	67 (47–83)	0 (0)
		SOF-VEL-VOX	8	17	17 (100)	6.3 (0.5)	–	–	–	–	PEG + RBV	0	100 (81–100)	0 (0)
		SOF-VEL-VOX	8	28	11 (39)	6.1 (0.6)	–	–	–	–	PI	3 (11)	89 (72–98)	1 (3.57)
		SOF-VEL-VOX	6	18	18 (100)	6.1 (0.7)	–	–	–	18 (100)	–	2 (11)	83 (59–96)	0 (0)
		SOF-VEL-VOX	8	19	19 (100)	6.3 (0.4)	–	–	–	–	PEG + RBV	0	100 (82–100)	3 (15.79)
		SOF-VEL-VOX	8	4	2 (50)	6.9 (0.2)	–	–	–	–	DAA	0	100 (40–100)	1 (25.00)
Lawitz et al. [29]	2016	SOF-VEL-VOX	6	34	0	6.2 (0.51)	–	–	–	34 (100)	–	10 (29)	71 (53–85)	0 (0)
		SOF-VEL-VOX	8	36	0	6.2 (0.55)	–	–	–	36 (100)	–	0	100 (90–100)	0 (0)
		SOF-VEL-VOX	8	33	33 (100)	6.0 (0.59)	–	–	–	33 (100)	–	2 (6)	94 (80–99)	1 (3.03)
		SOF-VEL-VOX + RBV	8	31	31 (100)	6.3 (0.47)	–	–	–	31 (100)	–	6 (19)	81 (63–93)	1 (3.23)
		SOF-VEL-VOX	12	31	0	6.4 (0.77)	17(55)	14 (45)	–	–	–	0	100 (89–100)	0 (0)
		SOF-VEL-VOX	12	32	32 (100)	6.0 (0.61)	12 (38)	20 (62)	–	–	–	0	100 (94–100)	0 (0)

HCV: hepatitis C virus; GT: genotype; SOF: Sofosbuvir; VEL: velpatasvir;VOX: voxilaprevir; RBV: ribavirin; SD: standard deviation; NS5A: Nonstructural protein 5 A inhibitors; NS3: NS3 protease inhibitors; NS5B: Non-structural protein 5B inhibitors; DAAs: direct acting antiviral agents; SVR12: sustained virologic response after treatment 12 weeks; 95% CI, confidence interval; § Grade 3 Hyperglycemia, serum glucose >250 mg/dl.

Table 2. Others grade 3 laboratory abnormality.

Author	Published years	Intervention	Week	Patients	Hemoglobin level <10 g/dl n (%)	Lymphocyte count <500/mm^3 n (%)	Neutrophil count <750/mm^3 n (%)	Platelet count <50,000/mm^3 n (%)	ALT >5 × ULN n (%)	AST >5 × ULN n (%)	Lipase level >3 × ULN n (%)	Total bilirubin level >2.5 × ULN (Hyperbilirubinemia) n (%)
Bourlière et al. [3]	2017	matched placebo	12	152	1 (0.66)	2 (1.32)	0 (0)	0 (0)	3 (1.97)	7 (4.61)	4 (2.63)	0 (0)
		SOF-VEL-VOX	12	263	2 (0.76)	0 (0)	1 (0.38)	2 (0.76)	0 (0)	2 (0.76)	6 (2.28)	1 (0.38)
		SOF-VEL-VOX	12	182	2 (1.10)	1 (0.55)	0 (0)	3 (1.65)	1 (0.55)	0 (0)	3 (1.65)	0 (0)
		SOF-VEL	12	151	1 (0.66)	1 (0.66)	2 (1.32)	2 (1.32)	0 (0)	0 (0)	1 (0.66)	0 (0)
Lawitz et al. [31]	2017	SOF-VEL-VOX	12	24	0 (0)	0 (0)	–	1 (4.17)	0 (0)	–	0 (0)	–
		SOF-VEL-VOX + RBV	12	25	6 (24.00)	1 (4.00)	–	1 (4.00)	1 (4.00)	–	1 (4.00)	–
Jacobson et al. [24]	2017	SOF-VEL-VOX	8	501	6 (1.20)	1 (0.20)	2 (0.40)	3 (0.60)	0 (0)	1 (0.20)	5 (1.00)	0 (0)
		SOF-VEL	12	440	3 (0.68)	3 (0.68)	2 (0.45)	2 (0.45)	1 (0.23)	0 (0)	3 (0.68)	1 (0.23)
		SOF-VEL-VOX	8	110	3 (2.73)	3 (2.73)	0 (0)	1 (0.91)	0 (0)	1 (0.91)	2 (1.82)	0 (0)
		SOF-VEL	12	109	0 (0)	1 (0.92)	1 (0.92)	1 (0.92)	0 (0)	1 (0.92)	1 (0.92)	0 (0)
Gane et al. [30]	2016	SOF-VEL-VOX	4	15	–	–	0 (0)	0 (0)	–	0 (0)	0 (0)	–
		SOF-VEL-VOX	6	15	–	–	0 (0)	0 (0)	–	0 (0)	0 (0)	–
		SOF-VEL-VOX	6	15	–	–	1 (6.67)	0 (0)	–	0 (0)	1 (6.67)	–
		SOF-VEL-VOX	6	30	–	–	0 (0)	0 (0)	–	1 (3.33)	3 (10.00)	–
		SOF-VEL-VOX	8	17	–	–	0 (0)	1 (5.88)	–	1 (5.88)	0 (0)	–
		SOF-VEL-VOX	8	28	–	–	0 (0)	0 (0)	–	0 (0)	1 (3.57)	–
		SOF-VEL-VOX	6	18	–	–	0 (0)	1 (5.56)	–	0 (0)	1 (5.56)	–
		SOF-VEL-VOX	8	19	–	–	1 (5.26)	0 (0)	–	0 (0)	1 (5.26)	–
		SOF-VEL-VOX	8	4	–	–	0 (0)	0 (0)	–	0 (0)	0 (0)	–
Lawitz et al. [29]	2016	SOF-VEL-VOX	6	34	0 (0)	–	–	0 (0)	0 (0)	–	–	0 (0)
		SOF-VEL-VOX	8	36	0 (0)	–	–	0 (0)	0 (0)	–	–	0 (0)
		SOF-VEL-VOX	8	33	0 (0)	–	–	1 (3.03)	0 (0)	–	–	–
		SOF-VEL-VOX + RBV	8	31	4 (12.90)	–	–	0 (0)	1 (3.23)	–	–	3 (9.68)
		SOF-VEL-VOX	12	31	0 (0)	–	–	0 (0)	0 (0)	–	–	0 (0)
		SOF-VEL-VOX	12	32	0 (0)	–	–	2 (6.25)	0 (0)	–	–	1 (3.13)

SOF: Sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; RBV: ribavirin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal.

Figure 2. Forest plots describing the incidence of grade 3 hyperglycemia following SOF/VEL/VOX therapy.

Figure 3. The forest plots of sensitivity analysis.

Figure 4. Forest plots for previously treated patients in subgroup analysis.

Figure 5. Subgroup analysis in hyperglycemia among with and without cirrhosis group. (A) cirrhosis, (B) without cirrhosis, (C) with and without cirrhosis.

Figure 6. Subgroup analysis by grade 3 event of varying interventions.

Figure 7. Subgroup analysis by different hepatitis C genotypes.

Figure 8. Risk of bias for available studies.

Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376(22):2134–2146.

 PubMed Web of Science ®Google Scholar

Lawitz E, Poordad F, Wells J, et al. Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral–experienced patients with genotype 1 hepatitis C virus. Hepatology. 2017;65:1803–1809.

 PubMed Web of Science ®Google Scholar

Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153(1):113–122.

 PubMed Web of Science ®Google Scholar

Gane EJ, Schwabe C, Hyland RH, et al. Efficacy of the combination of sofosbuvir, velpatasvir, and the NS3/4A protease inhibitor GS-9857 in treatment-naïve or previously treated patients with hepatitis C virus genotype 1 or 3 infections. Gastroenterology. 2016;151:448.e1–456.e1.

 Web of Science ®Google Scholar

Lawitz E, Reau N, Hinestrosa F, et al. Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with genotype 1 hepatitis C virus infection in an open-label, phase 2 trial. Gastroenterology. 2016;151:893.e1–901.e1.

 Web of Science ®Google Scholar

Data availability statement

No data is available for this study.