Gut 55(4): 529-535

PMC: PMC1856185

PMID: 16299039

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

M J Walsh, J R Jonsson, M M Richardson, School of Medicine, Southern Division, University of Queensland, Queensland, Australia

G M Lipka, Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia

D M Purdie, Northern California Cancer Center, Fremont, California, USA

A D Clouston, School of Medicine, Southern Division, University of Queensland, Queensland, Australia, and Histopath, Sydney, Australia

E E Powell, School of Medicine, Southern Division, University of Queensland, Queensland, Australia, and Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia

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

M J Walsh, J R Jonsson, M M Richardson, School of Medicine, Southern Division, University of Queensland, Queensland, AustraliaG M Lipka, Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, AustraliaD M Purdie, Northern California Cancer Center, Fremont, California, USAA D Clouston, School of Medicine, Southern Division, University of Queensland, Queensland, Australia, and Histopath, Sydney, AustraliaE E Powell, School of Medicine, Southern Division, University of Queensland, Queensland, Australia, and Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, AustraliaCorrespondence to: Dr E Powell
Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Qld, 4102, Australia; Elizabeth_Powell@ health.qld.gov.au

Revised 2005 Sep 22; Accepted 2005 Oct 25.

Abstract

Background

Interferon α (IFN‐α) 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‐α therapy and to determine hepatic expression of factors inhibiting IFN‐α 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‐α 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/m^{(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‐α.

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

Abstract

Despite an improvement in the efficacy of antiviral treatment in recent years, approximately 50% of patients infected with hepatitis C virus (HCV) genotype 1 and 20% of those with HCV genotype 3 fail to achieve sustained viral clearance.¹ Along with viral genotype and load,² various host genetic and biological factors have a role in the resistance to interferon alpha (IFN‐α) therapy. These host factors include sex, age, ethnicity, and genetic variation in human leucocyte antigens and cytokine production (reviewed by Gao and colleagues³). In addition, patients with advanced fibrosis have a decreased response to antiviral treatment.⁴

In order to increase the number of patients achieving a sustained virological response (SVR), there is a need to identify modifiable risk factors that impact on treatment efficacy. As a result, there is increasing interest in the role of obesity and hepatic steatosis in this setting. Steatosis may adversely affect the response to antiviral therapy.⁵⁶ In patients with non‐genotype 3 infection, the presence of steatosis was a predictor of failed treatment⁷⁸ and those with less steatosis were more likely to achieve SVR.⁶ However, it is unlikely that steatosis intrinsically impairs antiviral efficacy as steatosis associated with viral genotype 3 does not appear to adversely affect the response to treatment.⁶ Other investigators found that an elevated body mass index (BMI) in the obese range of >30 kg/m^{, rather than steatosis per se, was associated with therapeutic non‐response.}⁹

Obesity and steatosis are clearly interrelated and it remains unclear whether their reported effects are truly independent.¹⁰ A number of studies have found that patients with a higher body weight have reduced response rates following antiviral therapy.¹¹¹²¹³¹⁴ In the absence of weight based dosing, treatment failure in obese patients may be due to inadequate drug doses leading to lower serum levels of IFN‐α.¹⁵ Other mechanisms by which obesity may impair antiviral response such as by reducing the biological response to IFN‐α are not well understood. Interaction of IFN‐α with a cell surface receptor leads to a series of intracellular reactions that result in transcriptional induction of several antiviral and immunoregulatory genes.³ This IFN‐α‐activated signalling is negatively regulated by a number of inhibitory factors, including the suppressor of cytokine signalling (SOCS) family.³¹⁶¹⁷¹⁸ Several studies have found that patients with high tumour necrosis factor α (TNF‐α) levels have a poor response to IFN‐α therapy¹⁹²⁰²¹ and this may occur via induction of SOCS proteins²² that interfere with the interaction between the IFN‐α receptor and signalling proteins.¹⁶ Obesity and steatosis are known to be associated with elevated levels of TNF‐α²³²⁴ and more recent studies have shown increased hepatic expression of SOCS proteins in insulin resistant states.²⁵²⁶

The aims of this study were to evaluate the independent effects of obesity, hepatic steatosis, and obesity related metabolic factors on the response to antiviral therapy in patients with chronic HCV infection. In addition, we examined hepatic expression of the IFN‐α receptor 1 (IFN‐R1) and factors that may inhibit IFN‐α signalling (TNF‐α, SOCS‐3), and phosphoenolpyruvate carboxy kinase (PEPCK) as a marker of hepatic insulin sensitivity in obese and non‐obese subjects with chronic HCV.

Abbreviations

SOCS - suppressor of cytokine signalling

HCV - hepatitis C virus

IFN‐α - interferon α

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‐α - tumour necrosis factor α

GAPDH - glyceraldehyde‐3‐phosphate dehydrogenase

HOMA - homeostasis model of assessment

STAT - signal transducer and activator of transcription

Abbreviations

Footnotes

Funding for this study was provided by the Lions Medical Research Foundation, the National Health and Medical Research Foundation, and the Sasakawa Memorial Fund/Royal Children's Hospital Foundation.

Conflict of interest: None declared.

Footnotes

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