Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C

Table 1 Factors associated with the efficacy of interferon treatment

Factors	Main findings	Ref.
Classically identified viral and host factors
Age, HCV genotype, Viral load, Liver fibrosis	Older age, HCV genotype 1, high viral load, and advanced liver fibrosis were associated with poor treatment results	[3,4]
Viral factors
ISDR	Mutations of the ISDR (NS5A 2209-2234) were positively related to the HCV eradication with IFN-α monotherapy	[14]
Amino acid mutations of the core region (Nos. 70 and 91)	Mutations of amino acids were associated with a poor response to IFN-α plus RBV treatment	[15]
IRRDR	Mutations of the IRRDR (NS5A 2334-2379) were associated with a favorable response to the IFN-α plus RBV treatment	[16,17]
Drug resistant mutation1		[27,28]
Host factors
IL28B SNPs	The hero/minor allele of IL28B SNPs was related to a poor response to Peg-IFN-α plus RBV treatment	[18-20]

¹Resistant mutations to DAAs are only associated with the treatment efficacy of DAA-containing triple therapy. HCV: Hepatitis C virus; ISDR: Interferon sensitivity-determining region; IRRDR: Interferon/ribavirin resistance-determining region; RBV: Ribavirin; SNPs: Single nucleotide polymorphisms; Peg-IFN-α: Pegylated-interferon-α; IL28B: Interleukin 28B; DAA: Direct-acting antiviral.

Table 2 Possible involvement of anti-IFN-α neutralizing antibodies in the response to interferon-α treatment for chronic hepatitis C

Treatment	Cohort	Main results	Ref.
IFN-α monotherapy	47	Fifteen of 47 patients (31.9%) developed detectable levels of NAbs within two to eight months after starting treatment. Patients who developed anti-IFN NAbs showed poor responses to IFN (4/15: 26.6%) compared to antibody-negative patients (26/32: 81.3%) (P = 0.0009)	[29]
IFN-α monotherapy	63	Fifteen of 63 patients were positive for neutralizing anti-IFN-α NAbs. The responsive rate of all patients was 60.3% (38/63), while that of patients with anti-IFN NAbs was 13.3% (2/15), showing that NAbs development could significantly affect the therapeutic efficacy of IFN (P < 0.01)	[30]
IFN-α monotherapy	28	Among 28 patients treated with recombinant IFN-α-2a, anti-IFN-α NAbs were detected in 75% (6/8) of the patients who did not respond to IFN therapy. During IFN treatment, the mean ALT level of anti-IFN negative patients was decreased and continuously suppressed during treatment with the 3 MU of IFN-α-2a, while that of anti-IFN positive patients was reelevated without a dose-reduction of IFN	[31]
IFN-α monotherapy	84	In 84 patients with initial responses to IFN-α treatment, anti-IFN-α NAbs developed in 38.5% (5/13) of patients with breakthrough, as compared to 2.8% (2/71) of complete-responder patients (P < 0.0005) The emergence of anti-IFN-α NAbs three months after the initiation of therapy was the only factor to be predictive of breakthrough (RR = 9.5, 95%CI: 1.6-64.7, P = 0.007)	[32]
Peg-IFN-α plus RBV	42	A total of 42 non-response patients to previous conventional IFN treatment were re-treated with Peg-IFN-α-2a plus RBV. A decrease in HCV-RNA greater than 2 log10 copies/mL at week 12 relative to baseline values was not associated with the presence of anti-IFN-α NAbs (7/19, 36.8% in responders vs 6/23, 26.1% in non-responders at week 12; P = 0.73)	[35]
Peg-IFN-α plus RBV	129	A total of 129 patients who received Peg-IFN-α plus RBV were studied. Of the 47 patients who did not achieve an end of treatment response, seven patients (14.9%) were positive for anti-IFN-α NAbs, while no anti-IFN-α NAbs were detected in the 82 end of treatment responders (P = 0.0001). Anti-IFN-α NAbs were associated with a non-response to Peg-IFN-α plus RBV treatment, regardless of the patient IL28B-type and other treatment response-related characteristics	[36]

IFN: Interferon; Peg-IFN-α: Pegylated-interferon-α; RBV: Ribavirin; NAbs: Neutralizing antibodies; ALT: Alanine aminotransferase; RR: Relative risk; HCV: Hepatitis C virus; IL28B: Interleukin 28B.