Sustained Virological Response Prevents the
Development of Insulin Resistance in Patients With
Chronic Hepatitis C
Alessio Aghemo,1* Gian Maria Prati,1* Maria Grazia Rumi,2Roberta Soffredini,1Roberta D’Ambrosio,1
Emanuela Orsi,3Stella De Nicola,1Elisabetta Degasperi,1Valeria Grancini,3and Massimo Colombo1
Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), which is a con-
dition known to influence the progression of liver fibrosis and the response to pegylated
interferon (PEG-IFN)/ribavirin (RBV) therapy. We aimed to assess whether a sustained
virological response (SVR) after antiviral therapy prevents the development of IR in the
long term. Members of the Milan Safety Tolerability study cohort, who received PEG-
IFNa2a/RBV or PEG-IFNa2b/RBV, underwent a homeostasis model assessment (HOMA)
at the baseline and 24 months after treatment completion. For all patients (n 5 431), a
liver biopsy sample was scored for grading, staging (Ishak), and steatosis. At the baseline,
IR (HOMA value > 2) was detected in 48 patients (12%), and it was associated with body
weight (P 5 0.03), an HCV load < 0.6 3 106IU/L (P 5 0.006), fibrosis staging ? 4 (P 5
0.01), and moderate to severe steatosis (P 5 0.03). IR did not influence the rates of end-
of-treatment response (75% versus 69%, P 5 0.4), SVR (63% versus 60%, P 5 0.8), or
relapse (19% versus 24%, P 5 0.5). After treatment, IR developed in 49 of the 384 non-
diabetic patients (14%). Although the mean baseline and posttreatment HOMA values
were similar in SVR patients (1.11 6 0.8 versus 1.18 6 1.1, P 5 0.25), patients experienc-
ing treatment failure showed a significant increase in the mean HOMA value at the follow-
up visit (1.20 6 0.85 versus 1.49 6 1.3, P 5 0.007), and there was an increased rate of de
novo IR in non-SVR patients versus SVR patients (17% versus 7%, P 5 0.007). According
to a logistic regression analysis, treatment failure (odds ratio 5 2.81, 95% confidence
interval 5 1.39-5.67, P 5 0.004) and a 10% body mass index increase (odds ratio 5 6.42,
95% confidence interval 5 1.69-24.3, P 5 0.006) were significantly associated with the
development of de novo IR. Conclusion: In nondiabetic patients with chronic HCV,
the achievement of SVR with PEG-IFN and RBV prevents the development of de novo IR.
limited to just the liver because it also includes the de-
velopment of extrahepatic conditions such as non-
Hodgkin lymphoma and mixed essential cryoglobuli-
Moreover, growing evidence shows that
HCV interacts with glucose metabolism and leads to
the development of insulin resistance (IR), which in
fact is the background pathogenetic mechanism under-
nfection with hepatitis C virus (HCV) is a major
cause of morbidity and anticipated liver-related
mortality worldwide.1,2HCV morbidity is not
lying type 2 diabetes mellitus (T2DM).5The preva-
lence of T2DM is increased in patients with chronic
HCV infections versus the general population and
patients with liver diseases of various etiologies.6HCV
can promote IR, regardless of liver disease severity,
through interactions with different components of the
insulin signaling pathway or with factors involved in its
regulation.7HCV core protein reduces the expression of
insulin receptor substrate 1 (IRS1) and IRS2 and inter-
feres with the cellular response to insulin.8,9Clinically
Abbreviations: BMI, body mass index; ETR, end-of-treatment response; EVR, early virological response; HCV, hepatitis C virus; HOMA, homeostasis model
assessment; IR, insulin resistance; IRS, insulin receptor substrate; MIST, Milan Safety Tolerability; PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid
virological response; SVR, sustained virological response; T2DM, type 2 diabetes mellitus.
From the1A. M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS C? a Granda Ospedale Maggiore Policlinico;2Liver
Unit, San Giuseppe Hospital, and3Endocrinology and Diabetology Unit, Fondazione IRCCS C? a Granda Ospedale Maggiore Policlinico, University of Milan, Milan,
Received January 20, 2012; accepted May 15, 2012.
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HEPATOLOGY, Vol. 56, No. 5, 2012AGHEMO ET AL.1687