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. 2012:2012:582716.
doi: 10.1155/2012/582716. Epub 2012 Aug 27.

Restoration of innate and adaptive immune responses by HCV viral inhibition with an induction approach using natural interferon-beta in chronic hepatitis C

Y Kishida  1 , N Imaizumi, H Tanimura, Y Haruna, S Kashiwamura, T Kashiwagi
Affiliations

Restoration of innate and adaptive immune responses by HCV viral inhibition with an induction approach using natural interferon-beta in chronic hepatitis C

Y Kishida et al. Clin Dev Immunol. 2012.

Abstract

Chronic hepatitis C (CHC) is a serious medical problem necessitating more effective treatment. This study investigated the hypothesis that an induction approach with nIFN-beta for 24 weeks followed by PEG-IFN-alpha+ribavirin (standard of care: SOC) for 48 weeks (novel combination treatment: NCT) would increase the initial virologic response rate and restore innate and adaptive immune responses in CHC. Seven CHC patients with a high viral load and genotype 1b were treated with NCT. Serum cytokine and chemokine levels were evaluated during NCT. NCT prevented viral escape and breakthrough resulting in persistent viral clearance of HCVRNA. IL-15 was increased at the end of induction therapy in both early virologic responders (EAVRs) and late virologic responders (LAVRs); CXCL-8, CXCL-10, and CCL-4 levels were significantly decreased (P < 0.05) in EAVR but not in LAVR during NCT, and IL-12 increased significantly (P < 0.05) and CXCL-8 decreased significantly (P < 0.05) after the end of NCT in EAVR but not in LAVR. NCT prevented viral breakthrough with viral clearance leading to improvement of innate and adaptive immunity resulting in a sustained virologic response (SVR). NCT (n = 8) achieved a higher SVR rate than SOC (n = 8) in difficult-to-treat CHC patients with genotype 1 and high viral loads.

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Figures

Figure 1
Figure 1
Levels of serum cytokines (a), (a′) and chemokines (b), (b′) at baseline in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate types of ISDR. ISDR: interferon sensitivity determinin region. Significant difference: *P < 0.05, **P < 0.1.
Figure 2
Figure 2
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum cytokines (a), (a′) and chemokines (b), (b′) in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate type of ISDR (all patients). RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 3
Figure 3
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum cytokines (a), (a′), and chemokines (b), (b′) in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate types of ISDR (early virological responders). RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 4
Figure 4
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum cytokines (a), (a′) and chemokines (b), (b′) in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate types of ISDR (late virological responders). RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 5
Figure 5
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum CCL-4 in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate type of ISDR. RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 6
Figure 6
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum CXCL-8 in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate type of ISDR. RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 7
Figure 7
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum IL-10 in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate type of ISDR. RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 8
Figure 8
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum IL-15 in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate type of ISDR. RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 9
Figure 9
Effect of RBV plus PEG-IFN-alpha 2b using an “induction” approach with CPIT (NCT) on serum IL-12 in chronic hepatitis C patients with high viral load, genotype 1b (serotype I), and wild or intermediate type of ISDR. RBV: ribavirin, PEG-IFN: pegylated interferon, CPIT: cyclic and periodic interferon treatment, NCT: novel combination treatment. Significant difference: *P < 0.05, **P < 0.1.
Figure 10
Figure 10
Changes in serum HCVRNA level during the NCT and the SOC in chronic hepatitis C patients with genotype 1 and high viral loads. NCT: novel combination treatment; cyclic and periodic IFN treatment (CPIT) consisting of induction treatment with natural interferon-β followed by maintenance treatment with natural interferon-α for 24 wks as induction approach followed by SOC for 48 wks. SOC: standard of care; ribavirin plus pegylated interferon α 2b for 48 wks.
Figure 11
Figure 11
Rate of early viral responses in the initial 4 and 12 weeks (a) and end-of-treatment virological response and sustained virological response (b) in chronic hepatitis C patients with genotype 1 and high viral loads treated with the NCT and the SOC according to intention to treat. NCT: novel combination treatment; cyclic and periodic IFN treatment (CPIT) consisting of induction treatment with natural interferon-β followed by maintenance treatment with natural interferon-α for 24 wks as induction approach followed by SOC for 48 wks. SOC: standard of care; ribavirin plus pegylated interferon α 2b for 48 wks.
Figure 12
Figure 12
Changes in ALT level of peripheral blood during the NCT and the SOC in chronic hepatitis C patients with genotype 1 and high viral loads. NCT: novel combination treatment; cyclic and periodic IFN treatment (CPIT) consisting of induction treatment with natural interferon-β followed by maintenance treatment with natural interferon-α for 24 wks as induction approach followed by SOC for 48 wks. SOC: standard of care; ribavirin plus pegylated interferon α 2b for 48 wks.
Figure 13
Figure 13
Changes in platelets level of peripheral blood during the NCT and the SOC in chronic hepatitis C patients with genotype 1 and high viral loads. NCT: novel combination treatment; cyclic and periodic IFN treatment (CPIT) consisting of induction treatment with natural interferon-β followed by maintenance treatment with natural interferon-α for 24 wks as induction approach followed by SOC for 48 wks. SOC: standard of care; ribavirin plus pegylated interferon α 2b for 48 wks.
Figure 14
Figure 14
Changes in Hb level of peripheral blood during the NCT and the SOC in chronic hepatitis C patients with genotype 1 and high viral loads. NCT: novel combination treatment; cyclic and periodic IFN treatment (CPIT) consisting of induction treatment with natural interferon-β followed by maintenance treatment with natural interferon-α for 24 wks as induction approach followed by SOC for 48 wks. SOC: standard of care; ribavirin plus pegylated interferon α 2b for 48 wks.
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