Hepatitis C virus (HCV) infection is a major cause of

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: Clinical Significance of Metabolic Syndrome in the Setting of Chronic Hepatitis C Virus Infection IBRAHIM A. HANOUNEH,* ARIEL E. FELDSTEIN, ROCIO LOPEZ, LISA YERIAN, ANJANA PILLAI, CLAUDIA O. ZEIN, # and NIZAR N. ZEIN *Department of Internal Medicine, Department of Gastroenterology and Hepatology, Department of Pediatric Gastroenterology and Cell Biology, Department of Quantitative Health Sciences, and the Department of Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio; and the # Department of Gastroenterology and Hepatology, Case Western Reserve University, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio See Korenblat KM et al on page 1369 for companion article in the May 2008 issue of Gastroenterology. Background & Aims: The metabolic syndrome (MS) is a unique condition in which the underlying mechanism is related to insulin resistance. In hepatitis C virus (HCV) patients, insulin resistance has been linked to treatment failure. The aim of this study was to estimate the prevalence of MS in HCV patients undergoing antiviral therapy and to assess its predictive value in treatment outcome. Methods: All HCV treatment-naive patients who met the inclusion/ exclusion criteria were studied (n 228). MS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A logistic regression analysis was performed to study multivariable associations. The final model contained sex, ethnicity, body mass index, viral load, genotype, steatosis, fibrosis stage, and MS. Results: MS was present in 59 of 228 (26%) patients. Genotype 1 (P.002) and presence of steatosis (P <.001) were found to be associated significantly with MS. Overall, sustained virologic response (SVR) was achieved in 108 of 228 (47%) patients. Male sex, non-caucasian ethnicity, higher body mass index, high viral load, genotype 1, higher fibrosis stage, and MS were associated significantly with a lack of SVR. After adjusting for confounding variables, MS remained independently associated with a lack of SVR (P <.01). Specifically, subjects with MS were 3.8 (95% confidence interval, ) times more likely to fail treatment than those without MS. Conclusions: MS is seen frequently in patients with chronic HCV and is associated independently to lack of SVR. These findings support the concept that an aggressive intervention approach comprising lifestyle modification alone or in combination with drug treatment of the MS components may play an important role in improving antiviral responses in these patients. Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma throughout the world. Despite significant advances in knowledge of HCV biology and pathogenesis, a considerable number of infected patients will fail to achieve viral eradication after antiviral therapy and may develop complications of endstage liver disease. 1,2 The metabolic syndrome (MS), characterized by a constellation of factors including obesity, impaired fasting glucose, hypertension, and dyslipidemia, has become a major public health problem in the United States and many other parts of the world. A growing body of evidence suggests that several components of the MS may be important cofactors in chronic HCV-infected patients. 3,4 Insulin resistance (IR), the common denominator in the MS, has been shown extensively to be associated with chronic HCV infection with data supporting both viral- and host-mediated contributions. 5 A recent study using a mouse model transgenic for HCV core gene provided experimental evidence for a direct involvement of HCV in the development of IR and its associated hyperinsulinemia. 6 Moreover, IR measured by a homeostasis model of assessment (HOMA) has been implicated in the development of steatosis and progression of fibrosis in patients with chronic HCV Analogous to proposed mechanisms of hepatic fibrosis in patients with nonalcoholic steatohepatitis, hyperinsulinemia in HCV patients potentially may promote fibrogenesis through altered cytokine production including tumor necrosis factor alpha or by its direct effect on hepatic stellate cells. 11 In addition, IR has been linked to resistance to antiviral therapy in patients with chronic HCV infection, particularly those with HCV genotype 1. From the results of several cohort studies, it has been recognized that IR measured by HOMA is associated independently with poor response to antiviral therapy. In one prospective study, sustained virologic response (SVR) was only 36% in HCV genotype 1 patients with HOMA greater than 2 (IR) compared with an SVR rate of 49% in those with HOMA less than 2 (no IR). 12 Although the relationship between chronic HCV infection and IR has been shown both experimentally and in human studies, the association between HCV and MS remains poorly understood and the impact of MS on disease progression and treatment outcome in HCV patients has not been assessed carefully. MS is of particular interest because of its increasing prevalence among adults and children alike and for its potentially preventable and modifiable nature. Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; HCV, hepatitis C virus; HDL, highdensity lipoprotein; HOMA, homeostasis model of assessment; HVL, high baseline viral load; IR, insulin resistance; MS, metabolic syndrome; PEG IFN, pegylated interferon; Q25 Q75, 25 th percentile 75 th percentile; RBV, ribavirin; SVR, sustained virologic response by the AGA Institute /08/$34.00 doi: /j.cgh

2 May 2008 METABOLIC SYNDROME IN HCV 585 It is estimated that 22% of US adults 20 years or older meet the diagnostic criteria of MS. 15,16 The specific aims of this study were to estimate the prevalence of MS in our patients with chronic HCV undergoing therapy, to assess the interaction between MS and histologic findings, and to evaluate the predictive value of MS as an independent factor in identifying those who are likely to fail antiviral treatment. Patients and Methods Patient Population and Data Collection We identified all adult patients (age, 18 y) with chronic HCV infection who were treated for the first time with pegylated interferon (PEG IFN)-alfa and ribavirin (RBV) combination therapy at the Cleveland Clinic in Cleveland, Ohio, between 2002 and Patients with insufficient data to establish the presence or absence of MS at the initiation of antiviral therapy were excluded. MS was defined according to the National Cholesterol Education Program, Adult Treatment Panel III 16 as the presence of any 3 of the following 5 criteria: (1) serum triglyceride levels greater than 150 mg/dl or drug treatment for increased triglyceride levels; (2) serum high-density lipoprotein (HDL) cholesterol less than 40 mg/dl in men or less than 50 mg/dl in women, or drug treatment for low HDL; (3) blood pressure greater than 130/85 mm Hg or drug treatment for increased blood pressure; (4) fasting plasma glucose greater than 110 mg/dl or drug treatment for increased blood glucose levels; (5) abdominal obesity, defined as a waist circumference in men greater than 102 cm (40 inches), and in women greater than 88 cm (35 inches). The last trait in the Adult Treatment Panel III criteria (waist circumference) was replaced by body mass index (BMI) greater than 28.8 kg/m 2 in both men and women for the purpose of this study. This cut-off value for BMI was equivalent in a regression analysis to a waist circumference of 102 cm in a cross-sectional study. 17 Patients were excluded if they had received previous antiviral therapy for HCV. Patients who received PEG-IFN monotherapy or non PEG IFN with or without RBV were excluded. We also excluded subjects with other confounding liver diseases including autoimmune hepatitis, hemochromatosis, primary biliary cirrhosis, Wilson s disease, 1-antitrypsin deficiency, and neoplasia. Patients with hepatitis B or human immunodeficiency virus co-infection were not included in this study. All patients had no or minimal alcohol intake at the time of HCV therapy. Patients also were excluded if they were receiving corticosteroids, total parenteral nutrition or methotrexate, amiodarone, and valproic acid. Demographic data (age, sex, and race/ethnicity), pretreatment BMI, fasting serum glucose, triglyceride and HDL levels, systolic and diastolic blood pressure, HCV RNA level, HCV genotype, and liver histology were extracted from prospectively collected data for patients with chronic HCV infection seen at the Cleveland Clinic. Detailed medical history including a history of hypertension, hyperlipidemia, and diabetes, and their corresponding therapy were obtained from medical records. In addition, the cumulative dose of PEG IFN and RBV received, timing and reasons for dose reductions and discontinuations, occurrence of adverse events, and use of growth factors and antidepressants were obtained from HCV treatment-related data sheets filled out prospectively in all patients undergoing therapy. Antiviral Treatment Regimen Standard Food and Drug Administration approved dose regimens of PEG IFN alfa-2a (180 mcg/wk) or PEG IFN alfa-2b (1.5 mcg/kg/wk) and ribavirin (1000 mg/d if patient weight 75 kg, and 1200 mg/d if 75 kg) were initiated in all patients. Dose reductions and the use of growth factors were permitted for the management of anemia, neutropenia, and thrombocytopenia. Filgrastim 300 mcg weekly was used when the absolute neutrophil count decreased to less than 500/L. If the neutrophil count persisted below these limits, PEG IFN would be reduced. The PEG-IFN dose also was reduced for a platelet count of less than 30,000/L, and discontinued if platelet counts were less than 25,000/L. Erythropoietin 40,000 U subcutaneously was administrated once weekly if the hemoglobin level decreased to less than 10 g/dl. RBV dose was reduced by 200 mg if there was no improvement, and discontinued for hemoglobin less than 8 g/dl. Peg/RBV also were reduced or discontinued for disabling fatigue or severe depression not responsive to antidepressant therapy. Treatment duration was 48 weeks for patients with genotypes 1 and 4, and 24 weeks for genotypes 2 and 3. Treatment was discontinued in genotype 1 patients who did not have early virologic response at week 12 of therapy (defined by negative HCV RNA, or 2-log decrease in HCV RNA from pretreatment viral load). Hepatitis C Virus RNA and Laboratory Assays Quantitative polymerase chain reaction assay (Cobas Amplicor HCV Monitor Test, v 2.0; Roche, Nutley, NJ) was performed to detect HCV RNA at weeks 0, 12, 24, and 48 of therapy. Qualitative HCV RNA (Amplicor; Roche) testing was performed for those with an undetectable HCV RNA by qualitative assay at any time during therapy to confirm negativity of HCV RNA. For patients who were HCV RNA negative at the end of treatment, HCV RNA was repeated 6 months later to establish or exclude SVR. High baseline viral load (HVL) in this study was defined as an HCV RNA level that is greater than 800,000 IU/mL. Complete blood count was performed weekly for 1 month, and, if stable, on a monthly basis until the end of treatment. Liver function tests were performed monthly until end of treatment. Fasting serum glucose, plasma triglyceride and HDL levels, systolic and diastolic blood pressure, and BMI were measured at least twice before antiviral therapy and the average values were used to identify those with MS according to the Adult Treatment Panel III criteria. Liver Histology Liver biopsy was performed at least 1 month before the start of therapy. Hepatic steatosis was quantified as the percentage of hepatocytes that contained fat droplets, and accordingly assigned as negative when less than 5% of hepatocytes contained fat droplets, and positive when greater than 5% of hepatocytes showed fat storage. Hepatic fibrosis (stage) was assessed by the Ludwig Batts scoring system, and accordingly assigned using a scale of 0 to 4 (F0, absent; F1, portal fibrosis; F2, focal bridging fibrosis; F3, marked bridging fibrosis; F4, cirrhosis).

3 586 HANOUNEH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 5 Table 1. Baseline Clinical Characteristics in Study Patients Compared With Patients Who Were Excluded From the Study Characteristic Study patients (n 228) Excluded patients (n 173) P value Age a 52 (47 55) 51 (48 55).96 Caucasians 176 (77%) 134 (77%).95 Men 121 (53%) 102 (59%).24 Genotype (70.6%) 105 (69.9%).88 HVL 106 (46.5%) 78 (45.1%).78 BMI a 27.7 ( ) 28.3 ( ).48 Advanced hepatic fibrosis was defined as the presence of F3 or F4 according to the Ludwig Batts scoring system. Statistical Analysis Descriptive statistics were computed for all factors. These included median, 25th and 75th percentiles for continuous variables, and frequencies for categoric factors. The Wilcoxon rank-sum test was used to assess statistical differences in continuous or ordinal factors between subjects who achieved SVR and those who did not. For categoric factors, the Pearson chi-square or the Fisher exact tests were used. The same was performed to study associations with MS and advanced fibrosis (F3 and F4). A logistic regression analysis was performed to study multivariable associations. The final model for treatment failure included ethnicity, obesity, genotype, metabolic syndrome, HCV RNA, steatosis, and fibrosis. Statistical significance was considered for a P value of less than.05. SAS version 9.1 software (SAS Institute, Cary, NC) was used to perform all analyses. Results Patient Characteristics A total of 401 HCV patients were treated with antiviral medications during the time period from which study patients were identified. A total of 173 subjects (43%) were excluded for having one or more exclusion factors. Reasons for exclusion included previous antiviral treatment (n 23), type of therapy given (n 11), inadequate follow-up evaluation to establish the presence or absence of SVR (n 48), having other confounding liver disease or human immunodeficiency virus co-infection (n 21), and solid organ transplant recipients (n 7). Another reason for exclusion was missing pretreatment data to establish the diagnosis of MS (missing triglyceride/hdl values [n 34], missing BMI [n 12], missing fasting glucose level [n 14], or missing blood pressure [n 3]). To minimize a potential selection bias, we compared clinical characteristics of excluded patients with those who fulfilled inclusion/exclusion criteria. Demographic characteristics including age, race distribution, sex distribution, genotype, and pretreatment HCV RNA levels of 174 excluded patients were similar to the 228 patients included in the study (Table 1). The baseline characteristics of our study patients who fulfilled inclusion criteria are shown in Table 2. The median age was 52 years; and most (77%) were Caucasians with a predominant genotype 1 infection (70%). Baseline liver biopsy before initiation of antiviral therapy was available in 196 (84.2%) patients, with a median time of 5 months (25 th percentile 75 th percentile [Q25 Q75], 2 9 mo) between liver biopsy and initiation of antiviral therapy. Of 196 biopsy specimens, 104 (53%) had steatosis involving greater than 5% of the hepatocytes, and 52 (26.5%) had advanced fibrosis. High baseline HCV RNA levels (HVL) was present in 106 (46.5%) patients. Seventy-three patients (32%) were obese at the initiation of antiviral therapy (BMI, 30 kg/m 2 ), with a median BMI of 28.4 kg/m 2. In addition, 51 (22%) had either glucose intolerance or type II diabetes mellitus (DM). Prevalence of the Metabolic Syndrome and its Relation to Histologic Findings Fifty-nine of 228 (26%) patients met the Adult Treatment Panel III criteria for the MS (Table 2). Patients with HCV genotype 1 had a higher prevalence of the MS than those with genotypes other than 1 (51 of 161 [31%] vs 8 of 67 [12%]; P.002) (Table 2). There was a racial difference in the prevalence of the MS, with a higher prevalence of the MS in non-caucasian patients compared with Caucasian patients, although the difference did not reach statistical significance (P.1). Table 2. Clinical Features of Study Patients With or Without MS Factor All patients (N 228) MS (N 59) No MS (N 169) Odds ratio (95% CI) P value Age a 52.0 ( ) 53.0 ( ) 52.0 ( ) 1.3 ( ).07 Men (%) 121 (53) 32 (54.2) 89 (52.7) 1.07 ( ).83 Non-Caucasian (%) 52 (23) 18 (30.5) 34 (20.1) 1.7 ( ).1 Genotype 1 (%) 161 (70.6) 51 (86.4) 110 (65.1) 3.4 ( ).002 HVL (%) 106 (46.5) 24 (40.7) 82 (48.5) 0.73 ( ).3 BMI a 27.7 ( ) 31.8 ( ) 26.2 ( ) 1.3 ( ).001 Triglyceride level a 101 ( ) 167 ( ) 95.0 ( ) 1.2 ( ).001 HDL level a 50.0 ( ) 43.5 ( ) 51.0 ( ) 0.86 ( ).12 GIT and/or DM (%) 51 (22.4) 41 (69.5) 10 (5.9) 36.2 ( ).001 Hypertension (%) 119 (52.2) 56 (94.9) 63 (37.3) 31.4 ( ).001 Steatosis (%) 104 (53.1) 39 (73.6) 65 (45.5) 3.3 ( ).001 Advanced fibrosis (%) 52 (26.5) 19 (35.9) 33 (23.1) 1.9 ( ).072 NOTE. Odds ratio for age corresponds to a 5-year increase, and odds ratio for triglyceride and HDL levels correspond to a 10-unit increase. GIT, glucose intolerance.

4 May 2008 METABOLIC SYNDROME IN HCV 587 Table 3. Factors Associated With Advanced Fibrosis Factor Advanced fibrosis (n 52) Mild fibrosis (n 144) P value Age a 54.0 ( ) 50.0 ( ).001 Triglyceride level a ( ) ( ).55 HDL level a 52.5 ( ) 50.0 ( ).69 MS (%) 19 (36.5) 34 (23.6).072 Men (%) 31 (59.6) 77 (53.5).45 Caucasian (%) 37 (71.2) 113 (78.5).29 Genotype 1 33 (63.5) 110 (76.4).072 Obese (%) 17 (32.7) 45 (31.3).85 HVL (%) 26 (50.0) 65 (45.1).55 GIT and/or DM (%) 19 (36.5) 26 (18.1).007 Hypertension (%) 30 (57.7) 73 (50.7).39 Steatosis (%) 29 (55.8) 75 (52.1).65 GIT, glucose intolerance. The MS was associated significantly with the presence of steatosis in liver biopsy (Table 2). Steatosis was present in 39 of 59 (73.6%) HCV patients in whom MS criteria were met compared with 65 of 169 (45.5%) of those without MS (P.001). However, there was no association between steatosis and advanced fibrosis by either univariable or multivariable analysis (Tables 3 and 4). Univariable and multivariable analysis of factors associated with advanced fibrosis are shown in Tables 3 and 4. In univariable analysis (Table 3), advanced fibrosis was associated with age (P.001) and diabetes (P.007). In addition, a trend toward an association between advanced fibrosis and MS (P.072), as well as non genotype 1 infection (P.072) was present. However, after adjusting for these features in multivariable analysis (Table 4), MS was not associated with advanced fibrosis (P.57). Age (P.007), DM (P.052), and non genotype 1 (P.018) remained significantly related to advanced fibrosis. Response to Therapy and Predictors of Response Overall, SVR was achieved in 108 of 228 (47%) patients. Subjects with genotype 1 were less likely to achieve SVR compared with non genotype 1 patients (58 of 161 [36%] vs 50 of 67 [74%]; P.001) (Table 5). Relative to Caucasians, non- Caucasians had a lower response rate (lower SVR) to antiviral therapy (11 of 52 [21%] vs 97 of 176 [55%]; P.001). In addition, women were more likely to achieve SVR compared with their male counterparts (59 of 107 [55%] vs 49 of 121 [40%]; P.027). Other predictors of treatment failure by univariable analysis included older age, high pretreatment viral load (.007), advanced fibrosis (.002), DM (P.001), obesity (P.015), and MS (P.001) (Table 5). Multivariable logistic regression analysis of relevant variables showed that genotype 1 (P.0001), non-caucasian race (P.001), advanced fibrosis (P.002), and MS (P.009) had lower odds of achieving SVR than their corresponding counterparts (Table 6). After controlling for ethnicity, obesity, genotype, baseline HCV RNA, steatosis, and fibrosis, subjects with MS were 3.8 times (95% confidence interval [CI], ) more likely to fail treatment than those without MS. Obesity alone, although associated with a lack of SVR by univariable analysis, was not associated significantly with treatment outcome in the multivariable regression analysis model (P.68). The significance of obesity as an independent predictor of SVR did not change by using a cut-off point of 30 kg/m 2 to define obesity instead of 28.8 kg/m 2 (data not shown). The association between MS and lack of SVR was evident across different subgroups of patients. HCV genotype 1 patients with MS were less likely to achieve SVR than those without MS (SVR, 11 of 51 [21.6%] vs 47 of 110 [42.7%]; P.009). Similarly, subjects with advanced fibrosis and MS were less likely to achieve SVR compared with those who had advanced fibrosis without MS (SVR, 2 of 19 [10.5%] vs 12 of 33 [36.4%]; P.057]. Finally, only 2 of 19 (5.6%) African American patients with MS achieved SVR compared with 10 of 34 (29.4%) African American patients without MS (P.07). Discussion Several earlier studies established an epidemiologic association between HCV and DM. 18,19 More recently, IR in the absence of frank DM has been linked to the development of complications and failure of therapy in patients with chronic HCV ,20 In genotype 1 infection, the rate of SVR was nearly twice as common in patients who did not have evidence of IR by HOMA test compared with patients with IR. 12 An unresolved issue is the optimal method and its reproducibility to measure IR to identify those who are less likely to benefit from antiviral therapy in routine clinical practice. There is considerable variation in the complexity and intensity of various methods used to measure IR and no single test is appropriate under all circumstances. 21 Although the gold standard test to measure IR is the euglycemic clamp, it is only useful for intensive physiologic studies and is not feasible to incorporate into clinical practice. 21 Other methods to measure insulin sensitivity are those derived from oral glucose tolerance tests, in which they rely on the measurement of plasma glucose and insulin concentrations, either from fasting values (HOMA and quantitative insulin sensitivity index), 21 or postload values. 21 However, those methods are based on measurement of fasting blood insulin, which may vary considerably from one laboratory to another. 15 The so-called MS (also called insulin-resistance syndrome)isthe most commonly encountered clinical consequence of IR. MS is associated more consistently with the risk for cardiovascular disease than its individual components (obesity, diabetes, hypertension, and lipid abnormalities) and associated more consistently with measurable IR than its individual components. 15 MS also is incorporated easily into routine clinical practice with no need for sophisticated or expensive assays. Table 4. Multivariable Logistic Regression Analysis of Factors Associated With Advanced Hepatic Fibrosis Factor Odds ratio (95% CI) P value MS 1.4 ( ).57 Non-1 genotype 2.6 ( ).018 Age (5-year increase) 1.5 ( ).007 GIT and/or DM 3.0 ( ).052 Ethnicity (other vs Caucasian) 1.6 ( ).26 Obesity (BMI 30 kg/m 2 ) 2.2 ( ).13 GIT, glucose intolerance.

5 588 HANOUNEH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 5 Table 5. Univariable Analysis of Factors Associated With Treatment Failure Factor No SVR (N 120) SVR (N 108) Odds ratio (95% CI) P value Age a 53.0 ( ) 50.0 ( ) 1.3 ( ).001 Male (%) 72 (60.0) 49 (45.4) 1.8 ( ).027 Non-Caucasian (%) 41 (34.2) 11 (10.2) 4.6 ( ).001 Genotype 1 (%) 103 (85.8) 58 (53.7) 5.2 ( ).001 Baseline HVL (%) 66 (55.0) 40 (37.0) 2.1 ( ).007 Obese (%) 47 (39.2) 26 (24.1) 2.0 ( ).015 Triglyceride level a ( ) 95.0 ( ) 1.04 ( ).16 HDL level a 50.0 ( ) 50.0 ( ) 1.03 ( ).97 DM (%) 40 (33.3) 11 (10.2) 4.4 ( ).001 Hypertension (%) 73 (60.8) 46 (42.6) 2.1 ( ).006 MS (%) 44 (36.7) 15 (13.9) 3.6 ( ).001 Steatosis (%) 59 (54.6) 45 (51.1) 1.2 ( ).63 Advanced fibrosis (%) 38 (35.2) 14 (15.9) 2.9 ( ).002 NOTE. Odds ratio for age corresponds to a 5-year increase and odds ratio for triglyceride and HDL levels correspond to a 10-unit increase. In the current study, MS was present in 25% of patients with chronic HCV infection, which is slightly higher than the prevalence of MS (22%) reported in 8814 adults in the United States participating in the National Health and Nutrition Examination Survey III. 16 The higher prevalence of MS in our study may be owing to the ability of HCV to induce IR, predisposing infected patients to a greater risk for the development of MS. Alternatively, it may reflect the small sample size or geographic differences because our population was derived from the Midwest region of the United States. The higher prevalence of MS in patients with HCV genotype 1 infection compared with those infected with non-1 genotypes is interesting and may suggest a specific role of HCV genotype 1 virus in inducing metabolic abnormalities such as IR. 22 It has been shown previously that steatosis associated with HCV genotype 1 infection is a marker of metabolic abnormalities including obesity, hyperlipidemia, or DM and has been termed metabolic fat. 23,24 In contrast, steatosis in patients with HCV genotype 3 is associated with viremia rather than metabolic abnormalities and has been termed viral fat. 23,24 Our findings support the association between HCV genotype 1 infection and metabolic abnormalities in infected individuals. Adjusting for relevant variables, we found that neither MS nor steatosis on liver biopsy specimen were associated with advanced hepatic fibrosis. Conversely, DM was associated strongly with advanced fibrosis by univariable and multivariable analysis consistent with previous studies It has been shown previously that higher serum glucose levels as well as overt DM are associated with advanced liver fibrosis as well as Table 6. Predictors of Treatment Failure: Multivariable Logistic Regression Analysis Factor Odds ratio (95% CI) P value Genotype ( ).0001 Non-Caucasian ethnicity 4.8 ( ).001 Advanced fibrosis 4.2 ( ).002 MS 3.8 ( ).009 Baseline HVL 2.2 ( ).029 Obesity (BMI 30 kg/m 2 ) 0.83 ( ).68 Steatosis 1.04 ( ).92 a higher fibrosis progression rate. 28 The impact of DM/hyperglycemic state on the rate of fibrosis progression was greater than that of obesity, consistent with the findings in this study. 28 It is not clear why non genotype 1 infection was associated independently with advanced fibrosis compared with genotype 1 infection, although this also has been noted in other studies, particularly for patients infected with HCV genotype-3 virus. 29,30 A major limitation of our study design was that it was based on a cross-sectional, single-time biopsy specimen. Future studies of the impact of MS on fibrosis progression in the setting of HCV should include paired or multiple biopsy specimens obtained from each individual over a period of time to accurately control for the length of follow-up evaluation and to minimize the potential effect of sampling error. The most clinically significant finding of this study was the association between MS and treatment outcome in patients with chronic HCV. MS was associated significantly with the lack of SVR by univariable and multivariable analysis. Adjusting for ethnicity, genotype, obesity, baseline HCV RNA, steatosis, and fibrosis, subjects with MS were 3.8 (95% CI, ) times more likely to fail treatment than those without MS. Accordingly and given the simplicity of its assessment in the clinical practice, MS could be used along with other established predictors of treatment failure to identify those who are less likely to benefit from antiviral therapy. Other factors that were associated independently with lack of SVR in this study included genotype 1, non-caucasian ethnicity, advanced fibrosis stage, and HVL, all of which have been identified previously in retrospective and prospective studies. Of interest is that although obesity was associated with treatment failure by univariable analysis, it was not associated independently with treatment outcome, adding to the controversy in current medical literature regarding the role of obesity in treatment outcome of HCV patients. In population-based studies, it was suggested that MS is present in only 60% of obese individuals (BMI, 30), 31 which may explain discrepancies among studies. In summary, MS is seen frequently in patients with chronic HCV and is associated with treatment failure in the setting of chronic HCV. This finding, especially if validated in larger trials, suggests that MS may identify patients who are less likely to benefit from antiviral therapy. Future studies are underway to

6 May 2008 METABOLIC SYNDROME IN HCV 589 explore the role of interventions used in patients with MS including weight loss, lipid-lowering agents, and insulin-sensitizing agents as adjuvant to maximize SVR in HCV patients. References 1. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358: Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002;36(Suppl 1):S47 S Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29: Bloomgarden ZT. Measures of insulin sensitivity. Clin Lab Med 2006;26: , vi. 6. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004;126: Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003;38: Monto A, Alonzo J, Watson JJ, et al. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002;36: Hwang SJ, Luo JC, Chu CW, et al. Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation. J Gastroenterol Hepatol 2001;16: Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33: Lonardo A, Adinolfi LE, Loria P, et al. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;126: Romero-Gomez M, Del MV, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005; 128: D Souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol 2005;100: Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 2006; 131: Kahn R, Buse J, Ferrannini E, et al. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28: Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287: Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108: Zein CO, Levy C, Basu A, et al. Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol 2005;100: Zein NN, Abdulkarim AS, Wiesner RH, et al. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. J Hepatol 2000; 32: Camma C, Bruno S, Di MV, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology 2006;43: Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med 2002;19: Camma C, Bruno S, Di Marco V, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology 2006;44: Lonardo A, Loria P, Adinolfi LE, et al. Hepatitis C and steatosis: a reappraisal. J Viral Hepat 2006;13: Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33: Alsatie M, Kwo PY, Gingerich JR, et al. A multivariable model of clinical variables predicts advanced fibrosis in chronic hepatitis C. J Clin Gastroenterol 2007;41: Papatheodoridis GV, Chrysanthos N, Savvas S, et al. Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis. J Viral Hepat 2006; 13: Noto H, Raskin P. Hepatitis C infection and diabetes. J Diabetes Complications 2006;20: Ratziu V, Munteanu M, Charlotte F, et al. Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol 2003;39: Hickman IJ, Powell EE, Prins JB, et al. In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy. J Hepatol 2003;39: Fartoux L, Chazouilleres O, Wendum D, et al. Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. Hepatology 2005;41: Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care 2004; 27: Address requests for reprints to: Nizar N. Zein, MD, Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Mail Code: A30, 9500 Euclid Avenue, Cleveland, Ohio Zeinn@ccf.org; fax: (216)