Role of IL28B for Chronic Hepatitis C Treatment Toward Personalized Medicine

Kentaro Matsuura; Tsunamasa Watanabe; Yasuhito Tanaka

J Gastroenterol Hepatol. 2014;29(2):241-249.

Conclusion

Application of GWAS technology has revealed an unexpected role of IL28B in HCV infection. This finding could provide a strong rationale for developing novel therapeutic strategies for HCV infection as well as furthering basic studies on IFN-λs. The IL28B genotype could assist clinical decision-making for the treatment of acute HCV infection. In the context of PEG-IFN/RBV therapy for CHC, IL28B genotypes are strongly associated with treatment efficacy in patients infected with HCV genotype 1 or 4, with some effects on other HCV genotypes. IL28B genotyping is also useful for pretreatment prediction of the outcome of DAA plus PEG-IFN/RBV therapy, especially in treatment-naïve patients. Moreover, the IL28B genotype may affect responses to IFN-free regimens. Future more aggressive treatments, such as quadruple therapy or potent DAA combinations might obscure the influence of IL28B, but IL28B genotyping will remain useful for making decisions on suitable regimens and treatment duration in patients in the forthcoming era of DAAs. The mechanisms by which IFN-λs are active against HCV infection must be elucidated through the functional analyses of IFN-λs in future.

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Conflicts of interests
Yasuhito Tanaka has research contracts with MSD (Merck Sharp & Dohme) and Chugai Pharmaceutical Co. Ltd. The remaining authors have no conflict of interests.

Financial support
This work was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare of Japan, and a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology.

Table 1. GWAS of associations between favorable *IL28B* genotype and SVR in PEG-IFN/RBV therapy
Study	Ref.	Population	GWAS/replication size	Significant SNP	Odds ratio	P value	HCV genotype
Ge et al.	[7]	European American, African American, Hispanic	1137/none	rs12979860	3.10	1.37 × 10⁻²⁸	1
Suppiah et al.	[8]	Australian, European	293/555	rs8099917	1.98	7.06 × 10⁻⁸	1
Tanaka et al.	[6]	Japanese	142/172	rs8099917	12.10	1.18 × 10⁻¹⁸	1
Rauch et al.	[27]	European	465/none	rs8099917	5.19	3.11 × 10⁻⁸	1–4

Favorable IL28B genotype means rs8099917 TT or rs12979860 CC genotype.
GWAS, genome-wide association study; IL28B, interleukin-28B; PEG-IFN, pegylated interferon; RBV, ribavirin; Ref., reference number; SNP, single nucleotide polymorphism; SVR, sustained virological response.

Table 2. Associations between favorable *IL28B* genotype and SVR in PEG-IFN/RBV-treated patients infected with HCV genotype non-1
Study	Ref.	Population	SNP	Number of patients	Odds ratio	P value	HCV genotype
Rauch et al.	[27]	European	rs8099917	230	1.58	0.18	2, 3
Mangia et al.	[36]	European	rs12979860	268	1.80	0.0046	2, 3
Sakamoto et al.	[37]	Japanese	rs8099917	129	3.01	0.013	2
Yu et al.	[38]	Taiwan	rs8099917	482	1.37	0.50	2
Moghaddam et al.	[39]	North European	rs8099917	281	0.91	N.S.	3
Asselah et al.	[40]	Egyptian, European, Sub-Saharan African	rs12979860	82	3.32	0.0008	4
Antaki et al.	[41]	Syria	rs8099917	182	4.17	< 0.0001	4
Abdo et al.	[42]	Saudi Arabia	rs12979860	129	1.5	0.008	4
Antaki et al.	[43]	Syria	rs8099917	49	1.04	0.9	5
Seto et al.	[44]	Hong Kong	rs8099917	60	N.A.	0.014	6

Favorable IL28B genotype means rs8099917 TT or rs12979860 CC genotype.
IL28B, interleukin-28B; N.A., not available; N.S., not significant; PEG-IFN, pegylated interferon; RBV, ribavirin; Ref., reference number; SNP, single nucleotide polymorphism; SVR, sustained virological response.

Table 3. Associations between favorable *IL28B* genotype and spontaneous clearance of HCV
Study	Ref.	Population	SNP	Number of patients	Odds ratio	P value	HCV genotype
GWAS
Rauch et al.	[27]	European	rs8099917	1362	2.31	6.07 × 10⁻⁹	1–4
Duggal et al.	[48]	European, African, others	rs12979860	1482	2.22	2.17 × 10⁻³⁰	N.A.
Candidate gene study
Thomas et al.	[9]	European, African	rs12979860	1008	3.03	< 1.00 × 10⁻¹²	1
Grebely et al.	[49]	Australian	rs8099917	163	3.78	4.4 × 10⁻²	1–4
Tillmann et al.	[50]	German women	rs12979860	190	N.A.	< 1.00 × 10⁻³	1b
Grebely et al.	[51]	Caucasian, Aboriginal, Asian, Black	rs12979860	632	2.26	< 1.00 × 10⁻³	1–4, 6

Favorable IL28B genotype means rs8099917 TT or rs12979860 CC genotype.
GWAS, genome-wide association study; HCV, hepatitis C virus; IL28B, interleukin-28B; N.A., not available; Ref., reference number.

Table 4. Associations between *IL28B* genotype and SVR in DAA plus PEG-IFN/RBV therapy
Drug	Ref.	Study population	Treatment arm	rs12979860 genotype
Drug	Ref.	Study population	Treatment arm	CC	CT	TT
Boceprevir	[13, 64]	SPRINT-2 (treatment-naïve)	BOC PR48	44/55 (80%)	82/115 (71%)	26/44 (59%)
Boceprevir	[13, 65]	RESPOND-2 (treatment-experienced)	BOC PR48	17/22 (77%)	48/66 (73%)	13/18 (72%)
Telaprevir	[14, 66]	ADVANCE (treatment-naïve)	TVR12	45/50 (90%)	48/68 (71%)	16/22 (73%)
	[12, 67]	REALIZE (treatment-experienced): overall	All TVR	60/76 (79%)	160/266 (60%)	49/80 (61%)
		prior relapse	All TVR	51/58 (88%)	100/117 (85%)	29/34 (85%)
		prior partial response	All TVR	5/8 (63%)	33/57 (58%)	10/14 (71%)
		prior null response	All TVR	4/10 (40%)	27/92 (29%)	10/32 (31%)
	[68]	Japanese (treatment-naïve and experienced)	All TVR	31/42 (84%)	CT+TT 10/34 (32.3%)
Simeprevir (TMC-435)	[69]	PILLAR (treatment-naïve)	SMV 75 mg	26/31 (84%)	50/64 (78%)	7/14 (50%)
Simeprevir (TMC-435)	[69]	PILLAR (treatment-naïve)	SMV 150 mg	34/35 (97%)	48/60 (80%)	8/12 (67%)
Faldaprevir (BI-201335)	[70]	SILEN-C1 (treatment-naïve)	FDV 240 mg	22/22 (100%)	CT+TT 34/48 (71%)

BOC, boceprevir; DAA, direct-acting antiviral; FDV, Faldaprevir; IL28B, interleukin-28B; PEG-IFN, pegylated interferon; RBV, ribavirin; Ref., reference number; SMV, simeprevir; SVR, sustained virological response; TVR, telaprevir.

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Role of IL28B for Chronic Hepatitis C Treatment Toward Personalized Medicine

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