Maria Winnock

Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients.

Detection and characterization of all focal lesions in the liver are critical for screening patients with chronic liver disease. The aim of this prospective study was to investigate the accuracy of magnetic resonance imaging (MRI) and spiral computed tomography for the diagnosis of hepatic nodules in cirrhotic patients when compared with pathological findings of the explanted liver. From February 1997 to July 1999, 34 cirrhotic patients waiting for orthotopic liver transplantation (OLT) (mean age, 53.5 ± 9.3 years; 24 males) were included. All patients had MRI and spiral computed tomography examinations, and findings were matched with the histological findings. Data analyses were made using the McNemar chi-square test. Mean time between radiological examination (MRI or spiral computed tomography) and OLT was 43.8 ± 39 days. A total of 88 nodules were found in the 34 patients: 54 hepatocellular carcinoma (HCC) (mean size, 18 ± 10 mm) in 21 patients, 22 dysplastic nodules (mean size, 10.7 ± 4.3 mm) in 11 patients, and 12 macroregenerative nodules in 13 patients. Lesion-by-lesion analyses showed that sensitivity of MRI and spiral computed tomography for nodule, HCC or dysplastic nodule diagnosis was 44.3 and 31.8% (P = 0.02), 61.1 and 51.9% (P = 0.2), and 27.3 and 0% (P = 0.04), respectively. Patient-by-patient analyses showed no statistical difference between spiral computed tomography and MRI for nodule diagnosis. In conclusion, in patients with liver cirrhosis, MRI is more accurate than spiral computed tomography for the detection of liver nodules and dysplastic nodules. However, tumour size is always a restricting factor for these two techniques, which are unable to detect small HCC in more than 60% of cases.

Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver

BACKGROUND/AIMSnHistological and biochemical iron overload has been reported in non-tumoral liver of most patients presenting an hepatocellular carcinoma (HCC) developed in non-cirrhotic liver (NCL). The aim of our study was to investigate HFE mutations in patients with HCC in NCL.nnnMETHODSnThirty-five patients with HCC in NCL were included either retrospectively or prospectively. Clinical data, iron and viral status, and HFE gene mutations were compared between groups with (I+, n = 19) or without histological iron overload (I-, n = 16).nnnRESULTSnTwenty per cent of patients were HBV or HCV positive. Fifty-four per cent had hepatocytic iron overload at histology. Mean hepatic iron concentration was 100.2 +/- 14.6 micromol/g in I+ versus 23.2 +/- 2.1 micromol/g in I- (p<0.001). Among the 19 I+ patients, eight mutations were found: two C282Y/C282Y, three C282Y/WT, two C282Y/H63D and one H63D/H63D. None of these mutations was found in the I- group. There was no significant difference concerning the H63D heterozygous mutation between I+ or I- patients.nnnCONCLUSIONSnIn patients with HCC in NCL, HBV and HCV markers are rare (20%), and mild iron overload is frequent (54%). In patients with HCC in NCL and iron overload, C282Y mutations are frequent (36.8% of cases) and significantly increased (p<0.009) compared to HCC in NCL without iron overload; these mutations are mostly heterozygous. H63D heterozygosity is not associated with liver iron overload. Because of the small size of the series, HFE C282Y mutation should be investigated on a larger scale in patients with HCC in NCL with iron overload in order to confirm this association.

Prevalence of and Factors Associated With Hepatic Steatosis in Patients Coinfected With Hepatitis C Virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les h??patites virales CO3 Aquitaine Cohort

Background:Hepatic steatosis is a common feature in liver biopsies from patients with chronic hepatitis C and is associated with fibrosis progression. Patients with HIV infection and hepatitis C virus (HCV) coinfection have more rapid progression of liver fibrosis than patients with HCV infection alone. The prevalence and factors associated with hepatic steatosis are not well defined in HCV-HIV-coinfected patients. Methods:Steatosis was assessed among 148 HCV-HIV-coinfected patients of the Aquitaine Cohort. Steatosis was graded as follows: none, mild (1%-10% of hepatocytes), moderate (11%-30%), severe (31%-60%), and massive (more than 60%). Epidemiologic, clinical, biologic, and therapeutic data were retrieved from the cohort database to investigate the risk factors. Results:Steatosis was present in 67% of patients (95% confidence interval [CI]: 59% to 74%) and was at least moderate in 30% (95% CI: 23% to 38%). Steatosis was macrovesicular or mixed (macro- and microvesicular) in 40.5% and 52.8% of patients, respectively. Necroinflammatory activity was the only factor independent of steatosis (adjusted odds ratio = 5.3, 95% CI: 1.6 to 17.9). When necroinflammatory activity was removed from the model, HCV genotype 3 and body mass index (BMI) were significantly associated with steatosis. Conclusions:Liver inflammation, HCV genotype 3, and BMI are associated with steatosis, a common finding in HCV-HIV-coinfected patients.

Functional characterization of liver-associated lymphocytes in patients with liver metastasis

BACKGROUNDnThe liver-associated lymphocytes (LAL) population is mainly composed of cells with natural killer (NK) activity expressing the CD3+/-CD56+ phenotype. No evident difference has been found in the phenotypic data between patients with benign or malignant liver disease. In this study, the cytotoxic pattern of this population has been characterized from patients who underwent an operation for benign or metastatic liver disease.nnnMETHODSnLAL were isolated by sinusoidal high-pressure lavage from partial hepatectomies. Phenotype was characterized by flow cytometry, and cytotoxicity was evaluated by standard 4-hour 51Cr release assays against NK and lymphokine-activated killer (LAK)-sensitive targets.nnnRESULTSnIn patients with benign liver disease, LAL showed spontaneous high levels of NK activity and LAK activity compared with peripheral blood lymphocytes. In patients with metastatic liver disease, no difference was observed in the levels of NK activity between LAL and peripheral blood, and the level of LAK activity was far lower than that expressed in patients with benign liver disease.nnnCONCLUSIONSnThese results show that the cytotoxic pattern of peripheral blood lymphocytes does not mirror that of LAL. In patients with benign liver disease, LAL are in a state of activation, whereas the decreased level of LAL cytotoxicity in patients with metastatic liver disease suggests that the cytotoxic activity of these cells could be inhibited by the presence of suppressive factors.

Human liver-associated lymphocytes: an overview.

Morphological and phenotypical data indicate that liver sinusoids contain a heterogeneous population of lymphocytes of which large granular lymphocytes are only one element. It is suggested that the term of liver‐associated lymphocytes (LAL), which encompasses all sinusoidal lymphocytes, be used for this fourth sinusoidal cell type.

Impact of protease inhibitors on intrahepatic hepatitis C virus viral load.

During chronic hepatitis C, hepatitis C virus (HCV) load in plasma was shown to be higher in HIV-co-infected than in immunocompetent patients [1]. The reason for this increased HCV replication is not known. It may be as a result of HIV-induced immune deficiency [2], although some authors did not find any correlation with the CD4 cell count [3]. A direct interaction between HCV and HIV was also hypothesized [4]. Protease inhibitors (PI) used in highly active antiretroviral therapy (HAART) have no HCV reduction effect during the first months of treatment [5-8]. However, a decrease in HCV plasma load was recently described in patients treated with HAART for a year [9,10]. We therefore investigated the potential impact of HAART on intrahepatic HCV load.

Immunohistochemical Detection of HCV in Cirrhosis, Dysplastic Nodules, and Hepatocellular Carcinomas with Parallel-Tissue Quantitative RT-PCR

Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process. Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR. A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC. These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.

Elevated coffee consumption and reduced risk of insulin resistance in HIV‐HCV coinfected patients (HEPAVIH ANRS CO‐13)

Molloy and colleagues report original results about the association between caffeine consumption and the low risk of insulin resistance (IR) and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD). These results are consistent with previous reports on the association between elevated coffee consumption (ECC) and a lower risk of fibrosis progression in other populations, including chronically infected hepatitis C virus (HCV) patients. In these HCV patients, an indirect protective effect of ECC on histological progression by the intermediary of a decrease in IR has never been investigated. The possible relationship between ECC and IR could also be assessed in populations like human immunodeficiency virus (HIV)HCV coinfected patients, where IR is common, multifactorial, and likely to predict negative liver disease outcomes. To test this hypothesis, we used enrollment data from the HEPAVIH ANRS CO-13 cohort of HIV-HCV infected patients. The study group consisted of 601 patients, 74% of whom were HIV-HCV coinfected through injected drug use. Median (interquartile range) age was 43 years (range, 40-46 years), 31% were female, 13% reported elevated alcohol consumption, and 26% of patients reported ECC (drinking 3 cups of coffee). Thirty-two percent of the patients presented with advanced liver fibrosis (F3/F4), and those with homeostasis model assessment (HOMA)-IR 2.5 and 3 accounted for 59% and 69%, respectively. In multiple logistic regression, ECC was significantly associated with HOMA-IR 3 (adjusted odds ratio [AOR] [95% confidence interval (CI)] 1⁄4 1.62 [1.03-2.57], P 1⁄4 0.04), after adjustment for body mass index, EAC, and liver fibrosis (F3/F4 vs. F0/F1/F2). When using a different cutoff for HOMA-IR ( 2.5), after multiple adjustment the association between ECC and HOMA-IR was confirmed, although it was less significant (P 1⁄4 0.07).). ECC was also significantly associated with lower levels of fibrosis (F3/F4 vs. F0/F1/F2, AOR [95% CI] 1⁄4 1.56 [1.04-2.34], P 1⁄4 0.03), independently of EAC and HOMA-IR 3. Despite some limitations, such as difficulty standardizing selfreported coffee intake and lack of data about other caffeinecontaining products, our results are consistent with the hypothesis of a positive impact of ECC on IR and on liver fibrosis progression in HIV-HCV coinfected patients. Further research will help to better elucidate the causal mechanisms of this relationship and reveal whether polyphenols contained in coffee are also implicated. The use of coffee extracts to slow NAFLD and fibrosis progression is certain to soon become a clinical research concern. M. PATRIZIA CARRIERI, PH.D. PHILIPPE SOGNI, M.D. JULIEN COHEN, M.D. MARC-ARTHUR LOKO, M.D. MARIA WINNOCK, PH.D. BRUNO SPIRE, M.D., PH.D. and the HEPAVIH Study Group INSERM, U912 (SESSTIM), Marseille, France Universit e Aix Marseille, IRD, UMR-S912, Marseille, France ORS PACA, Observatoire R egional de la Sant e Provence Alpes Côte d’Azur, Marseille, France Institut Cochin, Universit e Paris-Descartes, INSERM U567-CNRS (UMR 8104), Paris, France APHP, Hôpital Cochin, Service d’H epatologie, Paris University of Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France INSERM, ISPED, Centre INSERM U897-EpidemiologieBiostatistique, F-33000 Bordeaux, France

Ribavirin and abacavir drug interaction in HIV―HCV coinfected patients: fact or fiction?

Objective(s):To examine the impact of ribavirin and abacavir coadministration on hepatitis C virus (HCV) virological response and trough ribavirin plasma concentration (Cmin) in HIV–HCV coinfected patients. Design:Pharmacokinetic substudy on patients from the ANRS CO-13 HEPAVIH cohort. Methods:Patients receiving ribavirin–pegylated interferon for whom a ribavirin steady state Cmin was prospectively determined were included. Rapid virological response (RVR), early virological response (EVR) and sustained virological response (SVR) as well as HCV-RNA decline were evaluated. Results:Overall, 124 HIV–HCV coinfected patients (95% on antiretroviral therapy) were enrolled. Of these patients, 22% received abacavir. The overall median (interquartile range) ribavirin Cmin was 1.6u200amg/l (1.2–2.2) with no statistical difference between abacavir users and nonusers [1.5u200amg/l (0.99–2.1) and 1.7 (1.2–2.3), Pu200a=u200a0.15]. RVR and EVR were 52 and 72%, respectively. There was no difference observed in the proportion of abacavir users vs. nonusers achieving RVR (respectively 59 vs. 50%, Pu200a=u200a0.40) or EVR (72 vs. 73%, Pu200a=u200a0.94), or in the HCV-RNA decline at week 4 [−2.24 log10u200aIU/ml, (−3.58; −0.81) and −1.27 (−2.8; −0.47) Pu200a=u200a0.28] or at week 12 [−1.76 log10u200aIU/ml (−3.67; −0.35) and −1.85 (−3.13; −1.13) (Pu200a=u200a0.58)]. The SVR rate was 45% for abacavir users and 24% for abacavir nonusers, but the difference was not statistically significant (Pu200a=u200a0.059). Conclusion:In our study, there was no evidence that abacavir affected HCV treatment outcomes and the ribavirin Cmin was similar in abacavir users and nonusers, confirming the absence of pharmacokinetic interaction between abacavir and ribavirin. An abacavir-containing regimen is, therefore, a well tolerated treatment alternative for coinfected patients starting HCV treatment.

Impact of HCV treatment and depressive symptoms on adherence to HAART among coinfected HIV-HCV patients: results from the ANRS-CO13-HEPAVIH cohort.

BACKGROUNDnThe additional burden of HCV infection in HIV-HCV-coinfected individuals may have some consequences on adherence to HAART. Few studies have explored the pattern of correlates of non-adherence to HAART while simultaneously considering the impact of HCV treatment and depressive symptoms on adherence to HAART. We used longitudinal data to assess factors associated with non-adherence to HAART.nnnMETHODSnThe French national prospective cohort ANRS-CO13-HEPAVIH is a multicentrer cohort, which recruited 1,175 HIV-HCV-coinfected patients in 17 hospital outpatient units delivering HIV and HCV care in France between October 2006 and June 2008. For this analysis, we selected participants on HAART with self-reported data for adherence to HAART (n=727 patients, 1,190 visits). Data were collected using self-administered questionnaires and medical records. A mixed logistic regression model based on an exchangeable correlation matrix was used to identify factors associated with non-adherence to HAART.nnnRESULTSnPatients reported non-adherence to HAART in 808 (68%) of the 1,190 visits. Four variables remained associated with non-adherence to HAART after multivariate analysis: hazardous alcohol consumption, cocaine use and depressive symptoms, regardless of whether treatment for depression was being received. Finally, patients being treated for HCV infection were less likely to be non-adherent to HAART.nnnCONCLUSIONSnBesides the problem of polydrug use, two other dimensions deserve special attention when considering adherence to HAART in HIV-HCV-coinfected patients. Access to HCV treatment should be encouraged as well adequate treatment for depression in this population to improve adherence and response to HAART.