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

Clinical and Developmental Immunology. 2012; 2012, Article ID 582716, 15 pages doi: 10.1155/2012/582716

Kishida Y1, Imaizumi N1, Tanimura H1, Haruna Y2, Kashiwamura S3 and Kashiwagi T4

 

1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Osaka Kaisei Hospital, Osaka City, Osaka, Japan, 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Osaka Prefectural General Medical Center, Osaka City, Osaka, Japan, 3Labolatory of Host Defenses Institute for Advanced Medical Sciences, Hyogo College of Medicine and 4Department of Nuclear Medicine and PET-Center, Hyogo College of Medicin, Nishinomiya City, Hyogo, Japan

 

Abstract

Chronic hepatitis C (CHC) is a serious medical problem necessitating more effective treatment. This study investigated the hypothesis that an induction approach with natural (n) IFN-beta for 24 weeks followed by PEGIFN-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 wit 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 (EAVR) and late virologic responders (LAVR), 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.

 

Supplement:

HCVRNA serum concentrations have been shown to promptly decrease to undetectable levels with successful antiviral treatment, and remain negative throughout treatment and thereafter. The faster the virus becomes undetectable during therapy, the better the chance of achieving a SVR. The resolution of a HCV infection may restore impairments in innate and adaptive immunities. However, the issue of how to increase the initial virologic response rate has not yet been resolved. In a previous study, we showed that cyclic and periodic IFN treatment (CPIT) consisting of induction treatment with nIFN-beta for 2 weeks followed by maintenance treatment  with nIFN-alpha for 2 weeks overcame virologic breakthrough, and achieved an early virologic response (EVR) and an end treatment virologic response (ETVR). In addition to the improvement in innate immunity due to virologic clearance by CPIT during the initial course of therapy, persistent virologic clearance and the restoration of innate and adaptive immune responses by SOC were more likely to result in a higher rapid virologic response (RVR), EVR, ETVR, and SVR. On the basis of these findings, we conducted a pilot study in 7 CHC patients with genotype 1b, high viral loads, and a wild or intermediate type IFN sensitivity determining region (ISDR) to assess the efficacy, tolerability, and safety of treatment with SOC using an induction approach with initial virologic clearance induced by CPIT for 24 weeks (novel combination treatment: NCT) [1].

Little is known about the chemokine and cytokine response to HCV infection before, during, and after IFN treatment. With an aim to better understand the immunological determinants of the protective immune response to HCV infection, we performed an extensive analysis of the innate and adaptive immune responses in CHC patients with genotype 1b and high viral loads. We evaluated serum levels of cytokines and chemokines that mediate humoral and cellular immunities and inflammation, correlated them with disease activity, and characterized the immunomodulatory effects of therapy.

We also compared the efficacy and safety of NCT versus SOC in CHC patients with genotype 1b and high viral loads. NCT was well tolerated and enhanced RVR, complete EVR, ETVR, and SVR rates in difficult-to-treat CHC patients with genotype 1b and high viral loads, and showed less AEs than those in SOC. The rate of SVR was significantly higher (p=0.0435) among patients receiving NCT (75%) than those receiving SOC (37.5%). NCT was shown to be more effective and have less adverse effects than SOC among difficult-to-treat CHC patients with genotype 1b and high viral loads (Figure 1) [2].

Hepatitis C virus (HCV) persistence in the host results from inefficiencies in innate and adaptive immune responses. Innate immunity controls adaptive immune responses through a direct interaction and through the exchange of signals between immune cells belonging to both compartments.

This study investigated the hypothesis that an induction approach using CPIT with nIFN-beta may increase the initial virologic response rate and restore innate and adaptive immune responses in CHC patients with genotype 1b and a high viral load. Study 1 showed that NCT with an induction approach with nIFN-beta overcame the emergence of viral escape and breakthrough, resulting in the persistent viral clearance of HCVRNA, which lead to an improvement in innate and adaptive immune responses in difficult-to-treat CHC patients with genotype-1b, high viral loads, and wild or intermediate types of ISDR. The current results (Figure 1-4) showed that (1) the significantly lower levels (p<0.05) of IL-12 and significantly higher levels (p<0.05) of IL-10, CXCL-8, CXCL-10, CCL-4 and CCL-11 in CHC patients than in the controls at baseline suggested an impairment in innate and adaptive immunities in CHC patients, (2) the level of IL-15 was increased at the end of CPIT in both EAVR, and LAVR, CXCL-8, CXCL-10, and CCL-4 levels were significantly decreased (p<0.05) in EAVR, but not in LAVR during NCT, (3) the level of IL-12 increased significantly (p<0.05) and the level of CXCL-8 decreased significantly (p<0.05) after the end of NCT in EAVR, but not in LAVR, and (4) levels of IFN-gamma and TNF-alpha at baseline were higher than those in the controls. The results obtained in the present study suggest that initial early virologic clearance induced by CPIT before the use of SOC induced the restoration of DC function and improvements in the activation of NK cell as indicated by the up-regulation of IL-12 and IL-15 and down-regulation of CXCL-8, CXCL-10, CCL-4, and CCL-11 (Figure 2-5).

These results suggest that (1) early virological clearance by CPIT before the beginning of SOC induced the restoration of innate immune responses and to anti-viral responses, (2) persistent virologic clearance for more than 48 weeks with subsequent SOC induced the restoration of innate immune responses linked to adaptive immune responses  resulting in SVR and sustained biochemical response, and (3) CPIT improved the innate immune response; however, there was an insufficient improvement in the adaptive immune response in CHC during NCT. T cell responses were more likely to peak late in the course of treatment. Combination therapy for HCV has a transient effect on host virus-specific T cells in the blood. The induction of sustained T cell responses may require additional immune modulation later in therapy. Most antiviral compounds can induce a good end-of-therapy response rate that is often not sufficient to result in the effective immune-mediated elimination of the virus, which is required for a curative sustained virologic response.

The findings of this study support the concept that viral clearance early in the course of therapy with reduced virologic resistance is linked to the restoration of innate and adaptive immune responses, which suggests that agents providing the greatest viral suppression leading to extended RVR including nIFN-beta, IFN-lambda, direct-acting antiviral agents (DAAs) and new developing agents may be preferable for the initial early induction approach. Initial viral clearance induced by CPIT in combination with those agents may lead to an improvement in innate and adaptive immune responses, resulting in a higher rate of SVR in difficult-to-treat CHC patients with genotype 1b and a high viral load. Restoration of innate immune responses including the activation of NK cell activity may be a novel therapeutic strategy for chronic HCV infection.

 

Yutaka Kishida-1

Figure 1. Rate of early virologic responses in the 4, 12, and 24 weeks (A) and end-of–treatment virologic response, and sustained virologic response (B) in chronic hepatitis C patients with serotype 1 (genotype 1b) and high viral load treated with the NCT or the SOC according to intention-to-treatment. NCT; novel combination treatment, SOC; standard of care.

 

Yutaka Kishida-2

Figure 2. Levels of serum cytokines (A) (A’) and chemokines (B)(B’) at baseline in chronic hepatitis C patients with high viral loads, serotype 1 (genotype 1b), and wild or intermediate types of ISDR. ISDR; IFN sensitivity determining region. Significant difference: * p<0.05, ** p<0.1

 

Yutaka Kishida-3 Figure 3. Effect of NCT on serum IL-12 in chronic hepatitis C patients with high viral load, serotype 1 (genotype 1b) and wild or intermediate type of ISDR. NCT; novel combination tratment. Significant difference: * p<0.05, ** p<0.1.

 

Yutaka Kishida-4Figure 4. Effect of NCT on serum IL-15 in chronic hepatitis C patients with high viral load, serotype 1 (genotype 1b) and wild or intermediate type of ISDR. NCT; novel combination tratment. Significant difference: * p<0.05, ** p<0.1.

 

Yutaka Kishida-5Figure 5. Effect of NCT on serum CXCL-8 in chronic hepatitis C patients with high viral load, serotype 1 (genotype 1b) and wild or intermediate type of ISDR. NCT; novel combination tratment. Significant difference: * p<0.05, ** p<0.1.

 

 

References

1. Kishida Y, Haruna Y, Naitoh M, Katayama K, and Kashiwagi T. Multiple Cytokine

Profiling of the Therapeutic Responses to Ribavirin and Pegylated Interferon-alpha 2b Using an “Induction” Approach With Natural Interferon-beta in Difficult-to-treat Chronic Hepatitis C. J Interferon and Cytokine Research. 2009; 29( 6): 353-368.

2. Kishida Y, Imaizumi N, Tanimura H, Haruna Y, Kashiwamura S, and Kashiwagi T.

Restoration of Innate and Adaptive Immune Responses by HCV Viral Inhibition with an Induction Approach Using Natural Interferon-Beta in Chronic Hepatitis C. Clinical and Developmental Immunology. 2012; 2012, Article ID 582716, 15 pages doi: 10.1155/2012/582716

 

Contact:

Yutaka Kishida Ph.D., M.D., Director, Division of Gastroenterology and Hepatology,

Department of Internal Medicine, Osaka Kaisei Hospital. 1-6-10, Miyahara, Yodogawa-Ku, Osaka City, Osaka, 532-0003 Japan. e-mail:y-kishida@muse.ocn.ne.jp

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann