Véronique Grando-Lemaire

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Hepatocellular carcinoma without cirrhosis in the West: epidemiological factors and histopathology of the non-tumorous liver

BACKGROUND/AIM In the West, hepatocellular carcinoma rarely occurs in patients without cirrhosis. In these patients, epidemiological factors and the histopathology of the non-neoplastic liver are not well known. The aim of this study was to clarify these points. METHODS We studied 30 patients (26 men, 28-87 years) with hepatocellular carcinoma and histologically-proven non-cirrhotic livers. Serological markers of HBV and HCV infection, as well as alcohol and tobacco consumption were evaluated. Pathological changes in the non-tumorous liver (fibrosis, inflammation, steatosis, alcoholic hepatitis lesions, iron overload, and large cell dysplasia) were systematically assessed using semi-quantitative scores. RESULTS Twenty patients had alcohol intake > or =30 g/d and 16 were smokers. Serological HBV or HCV markers were positive in 10 patients. Only four patients had no exposure to alcohol or tobacco and no serological markers of HBV or HCV Histological examination showed that all livers had pathological changes. Seventeen patients (57%) had clearly-identified chronic liver disease: chronic hepatitis (n = 10) or alcoholic liver disease (n = 7). Non-specific and moderate pathological changes were observed in the 13 other patients (43%), with different degrees of fibrosis, activity, steatosis, and iron overload. Large cell dysplasia was present in 12 patients (40%). CONCLUSIONS In our study, all patients with hepatocellular carcinoma and non-cirrhotic livers had non-tumorous pathological liver changes, especially iron overload and large cell dysplasia. These results suggest that hepatocellular carcinoma originates from an abnormal histological background, even in non-cirrhotic liver.

Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis.

BACKGROUND & AIMS Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, increased leptin, and decreased adiponectin serum levels. METHODS We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m(2)) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC. RESULTS The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years (p=0.017) and of liver-related death or transplantation 15%, 15% and 29% (p=0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR=1.10, [1.01-1.21] p=0.026) and was a strong predictor of liver-related death or transplantation (HR=1.13, [1.07-1.21] p<0.0001). Serum levels of adiponectin and leptin were not associated with the outcome. CONCLUSIONS In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation.

Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis

Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver‐infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val‐superoxide dismutase 2 (SOD2), G‐463A‐MPO, or T‐262C‐CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow‐up (61.1 ± 2.7 months), 51 patients developed HCC, and 71 died. The T‐262C‐CAT dimorphism did not modify hepatic iron, HCC, or death. The GG‐MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1–10.1) for HCC and 3.6 (1.9–6.7) for death. Carriage of one or two Ala‐SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5‐year incidence of HCC was 34.4% in patients with both the GG‐MPO genotype and one or two Ala‐SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5‐year death rates were 37.6%, 11.6%, and 5%. Conclusion: The combination of the GG‐MPO genotype (leading to high MPO expression) and at least one Ala‐SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis. (HEPATOLOGY 2009.)

Effect of Long-term Propranolol Treatment on Hepatocellular Carcinoma Incidence in Patients with HCV-Associated Cirrhosis

Propranolol bears antioxidant, anti-inflammatory, and antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of hepatocellular carcinoma (HCC). We retrospectively assessed the impact of propranolol treatment on HCC occurrence in a cohort of 291 patients with compensated viral C (HCV) cirrhosis, prospectively followed and screened for HCC detection. Of the 291 patients included in the cohort, 93 patients [50 males: mean age, 59.5 ± 12 years; body mass index (BMI), 25.7 ± 4.4 kg/m2; and platelet count, 111 ± 53 Giga/L] developed esophageal varices (OV) or had OV at inclusion and 198 patients (111 males: mean age, 55.8 ± 13 years; BMI, 25.7 ± 5 kg/m2; platelet count, 137 ± 59 Giga/L) did not. Among patients with OV, 50 received treatment by propranolol. During a median follow-up of 54 months interquartile range (32–82), 61 patients developed an HCC. The 3- and 5-year HCC incidence was 4% and 4%, and 10% and 20% for patients treated and not treated by propranolol, respectively (Gray test, P = 0.03). In multivariate analysis, propranolol treatment was associated with a decrease risk of HCC occurrence [HR, 0.25; 95% confidence interval (CI), 0.09–0.65; P = 0.004], and was the only independent predictive factor of HCC occurrence in patients with OV (HR, 0.16; CI, 0.06–0.45; P = 0.0005). The benefit of propranolol was further supported by propensity scores analyses. Conclusion: This retrospective long-term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis. These findings need to be verified by prospective clinical trial. Cancer Prev Res; 5(8); 1007–14. ©2012 AACR.

A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis

BACKGROUND & AIMS Genetic dimorphisms modulate the activities of several pro- or antioxidant enzymes, including myeloperoxidase (MPO), catalase (CAT), manganese superoxide dismutase (SOD2), and glutathione peroxidase 1 (GPx1). We assessed the role of the G(-463)A-MPO, T(-262)C-CAT, Ala16Val-SOD2, and Pro198Leu-GPx1 variants in modulating HCC development in patients with HCV-induced cirrhosis. METHODS Two hundred and five patients with HCV-induced, biopsy-proven cirrhosis but without detectable HCC at inclusion were prospectively followed-up for HCC development. The influence of various genotypes on HCC occurrence was assessed with the Kaplan-Meier method. RESULTS During follow-up (103.2±3.4 months), 84 patients (41%) developed HCC, and 66 died. Whereas the Ala16Val-SOD2 or Pro198Leu-GPx1 dimorphisms did not modulate the risk, HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7-4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank <0.0001) or the homozygous CC-CAT genotype (HR=1.74 [1.06-2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank=0.02). Compared to patients with neither of these two at risk factors, patients with only the CC-CAT genotype had a HR of 2.05 [0.9-4.6] (p=0.08) and patients with only the GG-MPO genotype had a HR of 3.8 [1.5-9.1] (p=0.002), while patients with both risk factors had an HR of 4.8 [2.2-10.4] (p<0.0001). However, only the GG-MPO genotype was independently associated with the HCC risk in multivariate Cox analysis. CONCLUSIONS The high activity-associated GG-MPO genotype increases the rate of HCC occurrence in patients with HCV-induced cirrhosis.