Title: Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients
Abstract: Background & Aims: 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. Methods: 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. Results: A sustained virological response was associated with lower age, insulin resistance index, body mass index, and γ-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). Conclusions: Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin. Background & Aims: 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. Methods: 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. Results: A sustained virological response was associated with lower age, insulin resistance index, body mass index, and γ-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). Conclusions: Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin. Host and viral factors influence the sustained virological response (SVR) rate to combined interferon/ribavirin therapy. Low viral load and non-1 genotype are the most favorable viral factors,1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5860) Google Scholar whereas host factors, including HLA class I2Romero-Gomez M. Gonzalez-Escribano M.F. Torres B. Barroso N. Montes-Cano M.A. Sanchez-Munoz D. et al.HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C.Am J Gastroenterol. 2003; 98: 1621-1626Crossref PubMed Scopus (32) Google Scholar and II3Sim H. Wojcik J. Margulies M. Wade J.A. Heathcote J. Response to interferon therapy Influence of human leucocyte antigen alleles in patients with chronic hepatitis C.J Viral Hepat. 1998; 5: 249-253Crossref PubMed Scopus (33) Google Scholar, ethnicity,4Kinzie J.L. Naylor P.H. Nathani M.G. Peleman R.R. Ehrinpreis M.N. Lybik M. et al.African Americans with genotype 1 treated with interferon for chronic hepatitis C have a lower end of treatment response than Caucasians.J Viral Hepat. 2001; 8: 264-269Crossref PubMed Scopus (69) Google Scholar and body mass index (BMI),5Bressler B.L. Guindi M. Tomlinson G. Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C.Hepatology. 2003; 38: 639-644Crossref PubMed Scopus (332) Google Scholar could also influence SVR.6Civeira M.P. Prieto J. Early predictors of response to treatment in patients with chronic hepatitis C.J Hepatol. 1999; 31: 237-243Abstract Full Text PDF PubMed Google Scholar Indeed, overweight5Bressler B.L. Guindi M. Tomlinson G. Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C.Hepatology. 2003; 38: 639-644Crossref PubMed Scopus (332) Google Scholar and African American7Muir A.J. Bornstein J.D. Killenberg P.G. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites.N Engl J Med. 2004; 350: 2265-2271Crossref PubMed Scopus (501) Google Scholar patients have shown a characteristic resistance to combination therapy, and increased BMI has been identified as an independent variable associated with poorer response.5Bressler B.L. Guindi M. Tomlinson G. Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C.Hepatology. 2003; 38: 639-644Crossref PubMed Scopus (332) Google Scholar Experimental and clinical studies support a role of hepatitis C virus (HCV) infection in the development of insulin resistance.8Shintani Y. Fujie H. Miyoshi H. Tsutsumi T. Tsukamoto K. Kimura S. et al.Hepatitis C virus infection and diabetes direct involvement of the virus in the development of insulin resistance.Gastroenterology. 2004; 126: 840-848Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar Patients with mild chronic hepatitis have a higher homeostasis model of assessment insulin resistance index (HOMA-IR) than healthy controls matched for age and BMI.9Hui J.M. Sud A. Farrell G.C. Bandara P. Byth K. Kench J.G. et al.Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression.Gastroenterology. 2003; 125: 1695-1704Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar Also, insulin resistance has been implicated in fibrosis progression10Lonardo A. Adinolfi L.E. Loria P. Carulli N. Ruggiero G. Day C.P. Steatosis and hepatitis C virus mechanisms and significance for hepatic and extrahepatic disease.Gastroenterology. 2004; 126: 586-597Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar and steatosis development11Petit J.M. Bour J.B. Galland-Jos C. Minello A. Verges B. Guiguet M. et al.Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C.J Hepatol. 2001; 35: 279-283Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar in chronic hepatitis C infection. It is interesting to note that insulin resistance is frequently seen in very difficult to treat chronic hepatitis C patients, such as cirrhotics, African Americans, overweight patients, and co-infected human immunodeficiency virus (HIV)/HCV patients. The aim of this study was to analyze the effect of body composition, the leptin system, and insulin resistance, together with viral factors, on SVR in patients with chronic hepatitis C treated with interferon plus ribavirin.Materials and methodsPatient populationConsecutive patients from 5 Spanish hospitals were recruited and treated according to standard daily clinical practice. Patients (n = 159; 94 men [59.1%] and 65 women [41.9%]; mean age, 41.7 ± 11.1 years; range, 22–67 years) with biopsy-proven chronic hepatitis C, showing HCV RNA-positive and altered alanine aminotransferase levels, were treated with peginterferon plus ribavirin (alfa-2a, n = 85; alfa-2b, n = 74). Genotype distributions were as follows: genotype 1, n = 113; genotype 2, n = 7; genotype 3, n = 29; and genotype 4, n = 10 (Table 1).Table 1Characteristics of the Patients in the StudyVariableSustained responders (n = 85)Nonsustained responders (n = 74)P valueAge (y)39.7 ± 10.444.5 ± 10.9.006Cholesterol (mg/dL)177.2 ± 36.1165.9 ± 41.1.08Glucose (mg/dL)94.2 ± 8.997.3 ± 11.7.063Body mass index (kg/m2)25.4 ± 3.6527.1 ± 4.89.027Alanine aminotransferase (U/L)116.8 ± 126.7115.1 ± 106.3.92Aspartate aminotransferase (U/L)58.4 ± 46.670.1 ± 41.2.15γ-Glutamyltranspeptidase (U/L)46.8 ± 49.5106.7 ± 107.2.001Leptin (ng/mL)Male5.1 ± 3.9712.4 ± 13.7.048Female13.3 ± 10.520.5 ± 13.5.016Viral load (×103 copies)1351 ± 19361057 ± 1213.32Median fibrosis1.55 ± 1.012.21 ± 1.47.002HOMA-IR2.36 ± 1.853.76 ± 3.22.001C-peptide2.53 ± 1.643.28 ± 1.64.132Genotype 1 (n = 110)49 (43.4%)64 (56.6%).0001Genotypes 2 and 3 (n = 36)32 (88.8%)4 (11.1%)Genotype 4 (n = 10)4 (40%)6 (60%)SexMale51 (54.2%)43 (45.8%).51Female34 (52.3%)31 (47.7%)NOTE. Data are n (%) or mean ± SD. Open table in a new tab Fully informed written consent was obtained before entry into the study, and the hospital's ethics committee approved the protocol. The history of alcohol consumption was obtained by 2 clinical researchers by using a standardized interview. Although alcohol use is hard to measure because it is subject to considerable underreporting, patients with active alcohol consumption >80 g/day or those who showed features of alcoholic disease upon liver biopsy were excluded. No patient had been treated with antiviral drugs. Patients previously diagnosed as having type 2 diabetes mellitus or who had fasting glucose levels >7 mmol/L were also excluded.Laboratory investigationsAn overnight (12-hour) fasting blood sample was taken for routine analyses, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltranspeptidase, cholesterol, and triglycerides. All patients had positive anti-HCV, as measured with EIA3 (Abbott Laboratories, Chicago, IL); increased alanine aminotransferase; and positive HCV RNA in serum. Hepatitis B surface antigen, anti-hepatitis B core antibody, and anti-HIV were tested by using commercially available kits (Abbott Laboratories, Chicago, IL). All patients were negative for hepatitis B surface antigen and anti-HIV.Fasting samples of serum obtained after centrifugation were stored in aliquots at −70°C until assayed. Serum insulin levels were measured by electrochemiluminescence immunoassay by using an autoanalyzer (Elecsys 1010/2010; Elecsys Modular Analytics E170; Roche, Basil, Switzerland). Serum C-peptide levels were measured by a commercially available kit (Immulite; Diagnostic Products, Los Angeles, CA). Serum leptin was measured with commercially available enzyme-linked immunosorbent assay kits (Quantikine Human Leptin Immunoassay; R&D systems, Minneapolis, MN). The HOMA-IR was calculated on the basis of fasting values of plasma glucose and insulin according to the HOMA model formula: HOMA-IR=fasting insulin (mIU/L)×fasting glucose(mmol/L)÷22.5As previously recommended, insulin resistance was arbitrarily considered altered when it was >2.8Shintani Y. Fujie H. Miyoshi H. Tsutsumi T. Tsukamoto K. Kimura S. et al.Hepatitis C virus infection and diabetes direct involvement of the virus in the development of insulin resistance.Gastroenterology. 2004; 126: 840-848Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar The HOMA model has been validated and widely used for determining the degree of insulin resistance and strongly predicts the development of type 2 diabetes.12Bonora E. Formentini G. Calcaterra F. Lombardi S. Marini F. Zenari L. et al.HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects prospective data from the Verona Diabetes Complications Study.Diabetes Care. 2002; 25: 1135-1141Crossref PubMed Scopus (442) Google Scholar Height and weight were determined at baseline, and the BMI was calculated as weight (in kilograms) divided by height (in square meters).Liver histologyPercutaneous liver biopsy was performed under ultrasonographic control. We assessed grading and staging separately. The stage was defined according to the Scheuer fibrosis score, in which F0 indicated absence, F1 indicated enlarged portal tracts, F2 indicated periportal or portoportal septa, F3 indicated fibrosis with architectural distortion, and F4 indicated cirrhosis. Necroinflammatory activity was determined by combining scores for portal inflammation (0–4) and lobular necrosis (0–4). Steatosis was quantified as the percentage of hepatocytes that contained fat droplets: 0% (absent) to 100% (all hepatocytes containing fat droplets). To classify the patients, steatosis was assigned as grade 0 if there was no steatosis, grade 1 when <25% of hepatocytes contained fat droplets, grade 2 when 25%–50% showed steatosis, and grade 3 when >50% of hepatocytes showed fat storage. Because the clinical significance and pathogenic mechanisms implied in the development of steatosis are different according to genotype, we analyzed the relationships between steatosis and insulin resistance and the sustained response rate segregated by genotype.Virology assessmentsHCV genotyping was performed with INNO-LIPA HCV II kits (Innogenetics, Zwijnaarden, Belgium), which were used according to the manufacturer's instructions. An Amplicor-HCV-Monitor 2.0 (Perkin-Elmer, Norwalk, CT) was used to quantify the HCV RNA levels in serum. Serum samples were diluted for measurement when values were beyond the linear range of the method. The level of detection was 50 IU/mL, and all patients were HCV RNA positive.Treatment outcomesPatients were treated according to genotype for 6 months (genotypes 2 and 3) or 12 months (genotypes 1 and 4). Eighty-five patients received 180 μg of peginterferon alfa-2a weekly, plus ribavirin; 74 patients received peginterferon alfa-2b adjusted by weight (1.5 μg/kg body weight every week) together with ribavirin 800, 1000, or 1200 mg, according to body weight (1000 or 1200 mg/day) or genotype (genotype 3, 800 mg/day; genotype 1, 1000–1200 mg/day).In a randomly selected group of 50 patients, the HOMA-IR was measured at baseline, after 6 months of treatment, and at the end of follow-up. SVR was defined as serum HCV RNA negativity 6 months after the conclusion of treatment.Statistical analysesComparisons between groups were made by using the Mann-Whitney U test or the Student t test for continuous variables and the χ2 or Fisher exact probability test for categorical data. The Spearman coefficient was used to correlate numerical variables that were nonnormally distributed. All values are presented as means ± SD. A probability value of P < .05 was considered statistically significant. The paired t test was used to compare HOMA-IR at baseline, at 6 months, and at the end of follow-up. Logistic regression (backward logistic regression) was used in the multivariate analysis to determine the factors associated with sustained response. Variables included in the analyses were age, sex, hepatic steatosis, BMI, γ-glutamyltranspeptidase, leptin, insulin resistance, fibrosis, HCV RNA level, and genotype.ResultsFactors associated with sustained virological responsePatients with SVR were younger (39.7 ± 10.4 years vs. 44.5 ± 10.9 years; P = .006), had a lower HOMA-IR (2.36 ± 1.85 vs. 3.76 ± 3.22; P = .001), had a lower BMI (25.4 ± 3.65 kg/m2 vs. 27.1 ± 4.89 kg/m2; P = .027), had lower γ-glutamyltranspeptidase levels (46.8 ± 49.5 U/L vs. 106.7 ± 107.2 U/L; P = .001), and had lower serum leptin levels in men (5.1 ± 3.97 ng/mL vs. 12.4 ± 13.7 ng/mL; P = .048) and in women (13.3 ± 10.5 ng/mL vs. 20.5 ± 13.5 ng/mL; P = .016). There was no association with sex distribution, type of interferon, alcohol consumption, or cholesterol levels. The HCV viral load was similar in both groups. SVR was achieved in 43.4% (46/113) of genotype 1 patients vs. 89% (32/36) of genotype 2 and 3 patients (P = .0001). The SVR rate was 64.6% in mild fibrosis (F0–F2) and 27.8% in advanced fibrosis (F3–F4; P = .001). Also, the median fibrosis was lower between responders (1.41 ± 0.88 vs. 2.16 ± 1.39; P = .0001) (Table 1). Hepatocyte steatosis was associated with a poorer SVR rate in genotype 1 patients (18.2% vs. 53.7%; P = .001). However, necroinflammatory activity was not associated with the SVR rate.With reverse stepwise logistic multivariate regression analysis, the independent variables related to SVR were genotype (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.49–8.3; P = .001), HOMA-IR (OR, 1.82; 95% CI, 1.08–3.06; P = .012), and fibrosis (OR, 1.36; 95% CI, 1.01–1.84; P = .029). The SVR rate in genotype 1 patients segregated with respect to HOMA-IR was 60.5% (95% CI, 45.9%–75.1%; 26/43) if HOMA was <2, 40% (95% CI, 25.7%–54.3%; 18/45) if HOMA was between 2 and 4, and only 20% (95% CI, 4.3%–35.7%; 5/25) if HOMA was >4 (P = .004) (Figure 1).Factors associated with insulin resistanceInsulin resistance correlated with BMI (r = 0.51; P = .001), age (r = 0.33; P = .002), leptin levels (r = 0.41; P = .003), serum C-peptide (r = 0.86; P < .001), and fibrosis stage (r = 0.41; P = .001). Despite the BMI correlation with HOMA-IR, insulin resistance was found in 20 of 54 patients (37%) with a BMI <25 kg/m2. HOMA-IR was higher in patients infected by genotype 1 than by genotype 3a (3.26 ± 2.82 vs. 2.28 ± 1.83; P = .003), whereas no difference was seen in BMI or leptin levels with respect to genotypes. In genotype 1 patients, HOMA-IR correlated with hepatocyte steatosis (r = 0.40; P = .001). Neither necroinflammatory activity nor cholesterol levels were associated with insulin resistance. In multivariate analysis, by using reverse stepwise logistic regression, BMI (OR, 1.69; 95% CI, 1.15–2.49; P = .0006) and fibrosis (OR, 2.27; 95% CI, 1.1–5.26; P = .03) were the independent variables associated with insulin resistance.Insulin resistance and hepatitis C virus viremiaIn 50 patients, a group representative of the entire cohort (37 were infected by genotype 1, 28 received peginterferon alfa-2a, and 25 were sustained responders), the HOMA-IR was measured before treatment, at 6 months of treatment, and at the end of follow-up. Figure 2 shows the mean ± SD HOMA values segregated with respect to sustained responders (n = 25), nonresponders (n = 11), and relapsers (n = 14). The HOMA-IR index decreased during the first 6 months of treatment in patients who had achieved clearance of HCV RNA at month 6 (from 2.55 ± 2.52 to 1.85 ± 1.66; P = .09), but it remained unchanged in patients with HCV RNA positive at month 6 (3.65 ± 2.03 to 3.53 ± 1.85; P = not significant). BMI decreased in both groups from 25.6 ± 3.8 kg/m2 to 24.3 ± 4 kg/m2 (P = not significant) in HCV RNA-negative patients and from 26.7 ± 3.8 kg/m2 to 24.9 ± 4.1 kg/m2 (P = not significant) in HCV RNA-positive at month 6 of treatment. In nonresponders, treatment was stopped, and HOMA-IR remained unchanged on follow-up. In sustained responders, HOMA-IR continued to decrease, and the paired t test indicated statistical significance when comparing baseline HOMA-IR with the values at the end of follow-up (2.55 ± 2.52 vs. 1.50 ± 0.77; P < .05). Conversely, in relapsers, the HOMA-IR increased from 6 months to the end of follow-up (Figure 2). The type of peginterferon administered did not seem to influence the changes in glycemia, insulinemia, or HOMA-IR during or after treatment.Figure 2Clinical evolution of insulin resistance (HOMA-IR) during and after treatment according to virological status (nonresponders, relapsers, and sustained responders). The paired t test indicated statistical significance when baseline HOMA-IR values were compared with those at the end of follow-up in sustained responders (2.55 ± 2.52 vs. 1.50 ± 0.77; P < .05). NR, nonresponders; RR, relapsers; SVR, sustained virological responders.View Large Image Figure ViewerDownload (PPT)DiscussionInsulin resistance, advanced fibrosis, and genotype 1 are independent predictors of a poor response to antiviral therapy in chronic hepatitis C. It is interesting to note that insulin resistance seems to be a common denominator among groups of poor-response patients, such as those with cirrhosis4Kinzie J.L. Naylor P.H. Nathani M.G. Peleman R.R. Ehrinpreis M.N. Lybik M. et al.African Americans with genotype 1 treated with interferon for chronic hepatitis C have a lower end of treatment response than Caucasians.J Viral Hepat. 2001; 8: 264-269Crossref PubMed Scopus (69) Google Scholar or a high BMI,13Chang S.A. Kim H.S. Yoon K.H. Ko S.H. Kwon H.S. Kim S.R. et al.Body mass index is the most important determining factor for the degree of insulin resistance in non-obese type 2 diabetic patients in Korea.Metabolism. 2004; 53: 142-146Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar African Americans,14Misra A. Impact of ethnicity on body fat patterning in Asian Indians and blacks relation with insulin resistance.Nutrition. 2003; 19: 815-816Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar and those with HIV/HCV co-infection.15Duong M. Petit J.M. Piroth L. Grappin M. Buisson M. Chavanet P. et al.Association between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy.J Acquir Immune Defic Syndr. 2001; 27: 245-250Crossref PubMed Google Scholar Whether insulin resistance is a marker for patients who are very difficult to treat or whether it plays a role in interferon plus ribavirin resistance remains unclear. Other host factors associated with insulin resistance, such as increased BMI and hepatocyte steatosis, have also been observed to be associated with a poorer SVR rate.16Patton H.M. Patel K. Behling C. Bylund D. Blatt L.M. Vallee M. et al.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.J Hepatol. 2004; 40: 484-490Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar In this study, both variables were associated with impaired SVR in univariate statistical analysis. However, in the multivariate analysis, HOMA-IR remained as an independent variable, and BMI and steatosis did not enter into the statistical equation. Our data strongly suggest that HOMA-IR may assist in further refining the prediction of antiviral response in patients infected by genotype 1. HOMA-IR was higher in advanced fibrosis and in patients infected by genotype 1 and, despite these associations, these variables seemed to be independently related to SVR. Thus, HOMA-IR could be the best host marker to predict SVR to combined therapy, at least in genotype 1-infected patients. Also, because insulin resistance can be modified by changes in lifestyle habits and by insulin-sensitizer drugs, this could be a potential target for treatment in chronic hepatitis C. Baseline viral load was not associated with SVR. Genotype has been found to be a stronger factor associated with SVR than baseline HCV RNA levels.6Civeira M.P. Prieto J. Early predictors of response to treatment in patients with chronic hepatitis C.J Hepatol. 1999; 31: 237-243Abstract Full Text PDF PubMed Google Scholar Indeed, in the largest pivotal study from Fried et al,1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5860) Google Scholar baseline HCV RNA was associated with SVR in the entire group, but there was no difference according to low or high viral load when patients were segregated by genotype. In a multivariate analysis, baseline HCV RNA was not an independent variable related to SVR,1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5860) Google Scholar and a lack of association between the baseline viral load and the chance of achieving SVR has also been previously reported.2Romero-Gomez M. Gonzalez-Escribano M.F. Torres B. Barroso N. Montes-Cano M.A. Sanchez-Munoz D. et al.HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C.Am J Gastroenterol. 2003; 98: 1621-1626Crossref PubMed Scopus (32) Google Scholar, 5Bressler B.L. Guindi M. Tomlinson G. Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C.Hepatology. 2003; 38: 639-644Crossref PubMed Scopus (332) Google ScholarInterferon induces insulin resistance immediately after administration in healthy controls.17Koivisto V.A. Pelkonen R. Cantell K. Effect of interferon on glucose tolerance and insulin sensitivity.Diabetes. 1989; 38: 641-647Crossref PubMed Google Scholar In chronic hepatitis C patients treated for 2 weeks, interferon induces a decrease in glucose uptake by peripheral tissue and the liver.18Imano E. Kanda T. Ishigami Y. Kubota M. Ikeda M. Matsuhisa M. et al.Interferon induces insulin resistance in patients with chronic active hepatitis C.J Hepatol. 1998; 28: 189-193Abstract Full Text PDF PubMed Scopus (53) Google Scholar However, this effect disappears when analyzed after 3 months of treatment19Ito Y. Takeda N. Ishimori M. Akai A. Miura K. Yasuda K. Effects of long-term interferon-alpha treatment on glucose tolerance in patients with chronic hepatitis C.J Hepatol. 1999; 31: 215-220Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar or during follow-up at the conclusion of treatment.20Tai T.Y. Lu J.Y. Chen C.L. Lai M.Y. Chen P.J. Kao J.H. et al.Interferon-alpha reduces insulin resistance and beta-cell secretion in responders among patients with chronic hepatitis B and C.J Endocrinol. 2003; 178: 457-465Crossref PubMed Scopus (38) Google Scholar Thus, interferon-induced cytokine release could explain the acute increase of insulin resistance that disappears whether treatment is maintained. Furthermore, in patients who cleared HCV RNA, insulin resistance decreased significantly at the end of follow-up, and this provides support for a role of HCV in the development of insulin resistance in this group of patients, as has been reported in an experimental model.8Shintani Y. Fujie H. Miyoshi H. Tsutsumi T. Tsukamoto K. Kimura S. et al.Hepatitis C virus infection and diabetes direct involvement of the virus in the development of insulin resistance.Gastroenterology. 2004; 126: 840-848Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar Nevertheless, the underlying mechanisms are not completely understood. Tumor necrosis factor (TNF) has been implicated in the development of insulin resistance and could be up-regulated by chronic hepatitis C infection. Indeed, TNF levels could predict the risk of developing diabetes mellitus in patients with chronic hepatitis C,21Knobler H. Zhornicky T. Sandler A. Haran N. Ashur Y. Schattner A. Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association.Am J Gastroenterol. 2003; 98: 2751-2756PubMed Google Scholar and TNF levels correlate with HOMA-IR in cirrhotic and noncirrhotic HCV patients.22Maeno T. Okumura A. Ishikawa T. Kato K. Sakakibara F. Sato K. et al.Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection.J Gastroenterol Hepatol. 2003; 18: 1358-1363Crossref PubMed Scopus (79) Google Scholar Also, TNF has been found to be a marker for a poor response to interferon therapy.23Larrea E. Garcia N. Qian C. Civeira M.P. Prieto J. Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C.Hepatology. 1996; 23: 210-217PubMed Google Scholar As such, patients showing insulin resistance might display higher TNF levels and resistance to antiviral therapy. In vitro experiments with liver samples indicate that HCV infection leads to a postreceptor defect in insulin receptor substrate 1, thereby contributing to insulin resistance.24Aytug S. Reich D. Sapiro L.E. Bernstein D. Begum N. Impaired IRS-1/PI3-kinase signalling in patients with HCV a mechanism for increased prevalence of type 2 diabetes.Hepatology. 2003; 38: 1384-1392Crossref PubMed Scopus (298) Google Scholar Indeed, in a murine model that is transgenic for the HCV core gene and that shows high TNF production, HCV infection seemed to be associated with insulin resistance development, and anti-TNF treatment improved the insulin sensitivity in this model.8Shintani Y. Fujie H. Miyoshi H. Tsutsumi T. Tsukamoto K. Kimura S. et