Who Is More Likely to Respond to Dual Treatment With Pegylated-Interferon and Ribavirin for Chronic Hepatitis C?

A Gender-Oriented Analysis

V. Di Marco; L. Covolo; V. Calvaruso; M. Levrero; M. Puoti; F. Suter; G. B. Gaeta; C. Ferrari; G. Raimondo; G. Fattovich; T. Santantonio; A. Alberti; R. Bruno; C. Mussini; M. Mondelli; F. Donato; A. Craxì


J Viral Hepat. 2013;20(11):790-800. 

In This Article


At baseline, for each patient, age, gender, diagnosis of diabetes, body mass index (BMI) and waist circumference (WC) were recorded. Males with a WC of more than 102 cm, and females with a WC of more than 88 cm, were defined as patients with visceral obesity (VO). Haematologic and biochemical parameters were obtained. Whole blood in EDTA for genetic analyses and fasted serum samples for centralized virologic and metabolic investigations were collected and stored at −80 °C until the analysis. Genotyping for rs12979860 was carried out using the TaqMan SNP genotyping allelic discrimination method (Applied Biosystems, Foster City, CA, USA) as previously reported.[30] HCV genotyping was carried out by INNO-LiPA HCV II assay (Innogenetics, Zwijndrecht, Belgium). Serum HCV-RNA was quantified at baseline and at week 12 of therapy by reverse transcription-PCR using Cobas Amplicor HCV Monitor Test, v 2.0 (Roche, Basel, Switzerland). Qualitative HCV-RNA assessment was made at weeks 4, 24, 48 during treatment, and 24 weeks after stopping therapy, using Cobas Amplicor HCV, v2.0 (Roche; limit of detection: 50 IU/mL). In accordance with international guidelines,[8,29] rapid virologic response (RVR) was defined as undetectable HCV-RNA in serum at week 4 of therapy; early virologic response (EVR) was defined as serum HCV-RNA negativity or any >2 log10 decline in HCV-RNA levels at week 12 of therapy compared with baseline; and SVR as undetectable HCV-RNA in serum 24 weeks after stopping therapy.

Serum glucose and insulin levels were measured centrally by electrochemiluminescence immunoassay (Insulina Immulite 2000, Medical System SpA, Genova, Italy), and the HOMA-IR score was computed as basal serum insulin (mU/mL) × basal serum glucose (mm)/22.5, with serum glucose converted from mg to mmol by multiplying by 0.055. The HOMA-IR score was considered a continuous variable.

Liver biopsy specimens were scored by pathologists at each centre using standardized scores.[31–33] Regarding the grading of inflammation, mild inflammation was defined as an A1 METAVIR score or A1 Scheuer's score or Ishak's score lower than A6. Patients with an A2–A3 METAVIR score or A3–A4 Scheuer's score or Ishak's score equal to or greater than A6 were classified as patients with moderate/severe inflammation. Steatosis was classified as absent or present with a cut-off of 10% of the hepatocytes. The staging of liver fibrosis was defined as mild/moderate if patients had F1–F2 METAVIR score or F1–F2 Scheuer's score or Ishak's score of F1–F3. Patients with F3–F4 METAVIR score, F3–F4 Scheuer's score or Ishak's score F4–F6 were classified as having severe fibrosis.[34]

Statistical Analysis

All data were analysed on the intention-to-treat basis using SPSS 13.0 for Windows software (SPSS Inc., Chicago, IL, USA) and STATA (Stata Statistical Software: Release 10.0.; Stata Corporation, College Station, TX, USA). Differences between continuous variables, expressed as mean ± standard deviation (SD), were analysed by t-test, while chi-squared test and Fisher's exact test were used for dichotomous or categorical variables. The association between baseline features and SVR was evaluated using multiple logistic regression analysis to identify variables independently associated with SVR. The baseline variables included in the analysis were age, gender, BMI and visceral obesity, serum levels of ALT, gamma glutamil transferase (GGT), cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, glucose and insulin, HOMA-R score and diagnosis of diabetes, platelet counts, viral genotypes and serum HCV-RNA levels (dichotomized at 400 000 UI/mL) and genotypes of the rs12979860 SNP. In genotype 1 patients, we also evaluated features of liver biopsy and, particularly, absence vs presence of steatosis, grading of inflammation (mild inflammation vs moderate/severe inflammation), and staging of fibrosis (absent/mild/moderate vs severe/cirrhosis). We also assessed the RVR as predictive of SVR. Variables with a threshold value of P < 0.10 on univariate analysis were included in the model, and only variables with a threshold value of P < 0.05 were retained in the final model. The results were expressed as odds ratios (ORs) and their 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curves were applied to identify the area under the ROC curve (AUROC) of the individual variables independently associated with SVR, used to generate a prediction rule, in accordance with Hanley and McNeil's suggestions.[35]