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Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

¹ School of Medicine, Southern Division, University of Queensland, Queensland, Australia
² Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia
³ Northern California Cancer Center, Fremont, California, USA
⁴ School of Medicine, Southern Division, University of Queensland, Queensland, Australia, and Histopath, Sydney, Australia
⁵ School of Medicine, Southern Division, University of Queensland, Queensland, Australia, and Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia

Correspondence to:
Correspondence to:
Dr E Powell
Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Qld, 4102, Australia; Elizabeth_Powell{at}health.qld.gov.au

ABSTRACT
Background: Interferon (IFN-) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown.

Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN- therapy and to determine hepatic expression of factors inhibiting IFN- signalling in obese and non-obese subjects with chronic HCV.

Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN- or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment.

Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p<0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index 30 kg/m² (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014).

Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-.

Abbreviations: SOCS, suppressor of cytokine signalling; HCV, hepatitis C virus; IFN-, interferon ; IFN-R1, interferon receptor 1; PEPCK, phosphoenolpyruvate carboxy kinase; NR, non-response to antiviral treatment; RES, response to antiviral treatment; SVR, sustained virological response; BMI, body mass index; RT-PCR, real time-polymerase chain reaction; TNF-, tumour necrosis factor ; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HOMA, homeostasis model of assessment; STAT, signal transducer and activator of transcription

Keywords: insulin resistance; tumour necrosis factor; phosphoenolpyruvate carboxy kinase; suppressor of cytokine signalling; obesity; antiviral therapy; hepatitis C

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