Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients

Hepatology Unit, Hospital Universitario de Valme, Sevilla, Spain.
Gastroenterology (Impact Factor: 16.72). 03/2005; 128(3):636-41. DOI: 10.1053/j.gastro.2004.12.049
Source: PubMed


We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin.
Patients (n=159; 94 men; age, 41.7 +/- 11.1 years) with chronic hepatitis C (genotype 1, n=113; non-1 genotype, n=46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated.
A sustained virological response was associated with lower age, insulin resistance index, body mass index, and gamma-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (P=.0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49-8.3; P=.001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08-3.06; P=.012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01-1.84; P=.029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%-43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%-75.1%) genotype 1 patients without insulin resistance (P=.007; odds ratio, 3.12, 95% confidence interval, 1.42-6.89).
Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.

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    • "Recent studies on HCV indicate not only the presence of enormous genetic diversity but also the possession of large variations in genotype distribution (Anjum et al., 2013; Fu et al., 2012). We performed a phylo-geographic analysis to study the evolution of NS5B protein in accordance to geographical spread because a strong correlation is reported to exist between demographic factors, including ethnicity, with therapeutic outcomes (Manns et al., 2001; Fried et al., 2002; Romero-Gómez et al., 2005). To guarantee the consistency in rebuilding evolutionary events, NS5B from Hepatitis GB, the closest living relative to human HCV, was included in the analysis as out-group (Bukh et al., 1999). "
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    ABSTRACT: Hepatitis C virus (HCV) is considered as a foremost cause affecting numerous human liver-related disorders. An effective immuno-prophylactic measure (like stable vaccine) is still unavailable for HCV. We perform an in silico analysis of nonstructural protein 5B (NS5B) based CD4 and CD8 epitopes that might be implicated in improvement of treatment strategies for efficient vaccine development programs against HCV. Here, we report on effective utilization of knowledge obtained from multiple sequence alignment and phylogenetic analysis for investigation and evaluation of candidate epitopes that have enormous potential to be used in formulating proficient vaccine, embracing multiple strains prevalent among major geographical locations. Mutational variability data discussed herein focus on discriminating the region under active evolutionary pressure from those having lower mutational potential in existing experimentally verified epitopes, thus, providing a concrete framework for designing an effective peptide- based vaccine against HCV. Additionally, we measured entropy distribution in NS5B residues and pinpoint the positions in epitopes that are more susceptible to mutations and, thus, account for virus strategy to evade the host immune system. Findings from this study are expected to add more details on the sequence and structural aspects of NS5B protein, ultimately facilitating our understanding about the pathophysiology of HCV and assisting advance studies on the function of NS5B antigen on the epitope level. We also report on the mutational crosstalk between functionally important coevolving residues, using correlated mutation analysis, and identify networks of coupled mutations that represent pathways of allosteric communication inside and among NS5B thumb, finger, and palm domains.
    Journal of Molecular Recognition 02/2015; 28(8). DOI:10.1002/jmr.2466 · 2.15 Impact Factor
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    • "The methods to measure IR vary, and the observations made in HCV-infected persons are conflicting depending on the technique used. Measuring the HOMA-IR to assess IR (defined by an arbitrary threshold of 2) [51] is very convenient when large study populations are to be evaluated, but it seems to overestimate the proportion of patients with IR, as post-load IR and stimulation assays [52] [53] have suggested a lower prevalence and level of IR. However, the occurrence of IR in chronic hepatitis C patients without stigmata of the metabolic syndrome has been reliably confirmed using the euglycemic hyperinsulinemic clamp method, an otherwise laborious technique not suitable for routine diagnostic use [54] [55]. "
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    ABSTRACT: The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.08.003 · 11.34 Impact Factor
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    • "It is well established that infection with HCV can induce insulin resistance and fat accumulation in the liver and multiple molecular mechanisms have been described for this phenomenon.18,19 There is further evidence that this insulin resistance provides some sort of survival advantage for the virus.1,3,7,20,21 Such studies form the rationale for trials of insulin sensitizers in CHC with the assumption that reversing insulin resistance may deprive the virus of this advantage and hinder its replication.12,22 "
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    ABSTRACT: BACKGROUND Evidence indicates that insulin resistance results in poor sustained viral response (SVR) in patients with chronic hepatitis C (CHC). Metformin is an oral hypoglycemic agent which improves insulin resistance. METHODS We sought to determine if the addition of metformin to the treatment regimen could improve SVR in treatment-naïve CHC patients in a randomized, double-blind, placebo-controlled trial. We randomized 140 consecutive CHC patients to receive either metformin 500 mg three times a day or placebo in addition to pegylated interferon (PEG-IFN) and ribavirin (RBV). Only treatment-naïve subjects aged between 15 and 65 years of age were included. SVR was defined as no detectable HCV RNA six months after the end of treatment.Subjects who received at least one dose of PEG-IFN were included in the finala nalysis. RESULTS The SVR rate in the metformin group was 75% versus 79% in controls (intention-to-treat) which was not significantly different. Also, the difference between the placebo and metformin group was not significant in subsets of different genotypes or those with homeostasis model assessment of insulin resistance (HOMA-IR) levels greater than 2 or body mass index greater than 25. The most common complaint was gastrointestinal discomfort (13% in metformin group versus 4% in controls; p=0.002) that lead to discontinuation of metformin in 8 participants. CONCLUSION Although triple therapy with metformin, PEG-IFN and RBV is relatively well tolerated, the addition of metformin did not significantly improve viral response in CHC patients.
    Middle East journal of digestive diseases 01/2014; 6(1):13-7.
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