Brescia, Italy
Brescia, Italy

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Lacombe K.,French Institute of Health and Medical Research | Lacombe K.,University Pierre and Marie Curie | Lacombe K.,Saint Antoine Hospital | Boyd A.,French Institute of Health and Medical Research | And 12 more authors.
Hepatology | Year: 2013

Anti-hepatitis B virus (HBV) nucleos(t)ides analogs (NA) exert selective pressures on polymerase (pol) and surface (S) genes, inducing treatment resistance and increasing the risk of vaccine escape mutants. The rate of emergence for these mutations is largely unknown in patients coinfected with human immunodeficiency virus (HIV) and HBV undergoing dual-active therapy. In a 3-year, repeat-sampling, prospective cohort study, HBV viral genome sequences of 171 HIV-HBV coinfected patients, presenting with HBV viremia for at least one visit, were analyzed every 12 months via DNA chip. Logistic and Cox proportional hazard models were used to determine risk factors specifically for S gene mutations at baseline and during follow-up, respectively. HBV-DNA levels >190 IU/mL substantially decreased from 91.8% at inclusion to 40.3% at month 36 (P<0.001), while lamivudine (LAM) or emtricitabine (FTC) use remained steady (71.9%) and tenofovir (TDF) use expanded (month 0, 17.5%; month 36, 66.7%; P<0.001). The largest increase of any mutation class was observed in l-nucleoside-associated pol gene/antiviral-associated S gene mutations (cumulative incidence at the end of follow-up, 17.5%) followed by alkyl phosphonate-associated pol-gene (7.4%), immune-associated S gene (specifically any amino acid change at positions s120/s145, 6.4%), and d-cyclopentane-associated pol-gene mutations (2.4%). Incidence of l-nucleoside-associated pol-gene/antiviral-associated S gene mutations was significantly associated with concomitant LAM therapy (adjusted hazard ratio [HR], 4.61; 95% confidence interval [CI], 1.36-15.56), but inversely associated with TDF use (adjusted HR/month, 0.94; 95% CI,0.89-0.98). Cumulative duration of TDF was significantly associated with a reduction in the occurrence of immune-associated S gene mutations (HR/month, 0.88; 95% CI, 0.79-0.98). No major liver-related complications (e.g., fulminant hepatitis, decompensated liver, and hepatocellular carcinoma) were observed in patients with incident mutations. Conclusion: Vaccine escape mutants selected by NA exposure were frequent and steadily increasing during follow-up. Although the high antiviral potency of TDF can mitigate incident mutations, other antiviral options are limited in this respect. The public health implications of their transmission need to be addressed. (Hepatology 2013;53:912-922). © 2013 by the American Association for the Study of Liver Diseases.


Sukowati C.H.C.,Centro Studi Fegato | Sukowati C.H.C.,University of Trieste | Anfuso B.,Centro Studi Fegato | Torre G.,Hepatology Unit | And 4 more authors.
PLoS ONE | Year: 2013

Although the CD90 (Thy-1) was proposed as biomarker of several tumors and cancer stem cells, the involvement of this molecule in the progression of hepatocellular carcinoma (HCC) and other less frequent hepatic neoplasms is still undefined. The distribution of CD90 was investigated both in in vivo (human tissues samples) and in vitro (human HCC cell line JHH-6). A total of 67 liver tumors were analyzed: 51 HCC, 6 cholangiocarcinoma and 10 hepatoblastoma. In all cases, paired tissue sample of both the tumor and cirrhotic liver was available. Hepatic tissue obtained in 12 healthy livers was used as control. CD90 gene expression was studied by RT-qPCR, protein expression was assessed by quantitative Western Blot, immunofluorescence and flow cytometry. The CD90 expression analysis showed a significant increment in tumor compared to both its paired cirrhotic tissue and normal liver (p<0.05 and p<0.001, respectively). This increase was accompanied by the up-regulation of stromal component in the cancer, as demonstrated by alpha smooth muscle actin staining. In vitro analysis of JHH-6 cell line showed a higher proliferation capacity of CD90+ compared to CD90- cells (p<0.001), also noticed in 3D clonogenic assay (p<0.05), associated by a significant higher expression of the promoting factors (hepatocyte growth factor, fibroblast associated protein and alpha smooth muscle actin 2). A higher expression of the breast cancer resistance protein was found in CD90+ subpopulation while the multidrug resistance protein 1 showed an opposite behavior. Collectively, these results point to the importance of CD90 in the HCC. © 2013 Sukowati et al.


Boyd A.,French Institute of Health and Medical Research | Gozlan J.,University Pierre and Marie Curie | Maylin S.,Laboratoire Of Virologie | Maylin S.,French Institute of Health and Medical Research | And 12 more authors.
Hepatology | Year: 2014

Tenofovir (TDF) is considered the ideal treatment for patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, certain coinfected patients exhibit incomplete viral suppression, with persistent, and sometimes transient, bouts of HBV replication. The reasons for this, including clinical effect, are unclear. A total of 111 HIV-HBV-infected patients undergoing TDF-containing antiretroviral therapy were prospectively followed. Serum HBV-DNA viral load, hepatitis surface (HBsAg) and e antigen (HBeAg) status were obtained at baseline and every 6-12 months. Amino acid (aa) changes on the polymerase gene were assessed using direct sequencing after nested polymerase chain reaction in patients with persistent viremia (PV). After a median of 74.7 months (interquartile range: 33.4-94.7), virological response (VR; <60 IU/mL) occurred in 96 of 111 (86.5%) patients. Of these, 86 of 96 (89.6%) remained completely undetectable during follow-up (stabilized VR). The remaining 10 of 96 (10.4%) patients had a transient blip of detectable HBV-DNA (transient PV), during which time 9 of 9 (100%) with available samples had detectable plasma TDF. Low-level PV (LL-PV; 61-2,000 IU/mL) was observed in 11 of 111 (9.9%) patients, the majority of which had detectable plasma TDF (8 of 9; 88.9%). High-level PV (>2,000 IU/mL) was rare (4 of 111; 3.6%) and was associated with nonadherence. At TDF initiation, patients with stabilized VR had significantly higher nadir CD4+ count, compared to those with transient PV (P=0.006) or LL-PV (P=0.04). No consistent aa changes, other than those associated with lamivudine resistance, were observed in patients with persistent viremia. Importantly, HBeAg loss, HBeAg seroconversion, and HBsAg loss only occurred in patients with stabilized VR. Two patients with stabilized VR developed hepatocellular carcinoma and 2 with LL PV died, 1 of a liver-related cause. Conclusion: Suboptimal HBV control during TDF treatment has a negative effect on serological outcomes, but not necessarily clinical events. Immunoregulation may provide more insight into this phenomenon. (Hepatology 2014;60:497-507) © 2014 by the American Association for the Study of Liver Diseases.


Stickel F.,Hepatology Unit | Stickel F.,University of Bern | Seitz H.K.,University of Heidelberg
Journal of Gastrointestinal and Liver Diseases | Year: 2013

Among heavy drinkers with liver disease, the development of severe alcoholic hepatitis (AH) is a serious complication. Prognosis is grave and associated with a high mortality due to liver failure, hepatorenal syndrome or intractable sepsis. Clinically, AH presents as a syndrome of progressive inflammatory liver injury in patients with recent or ongoing heavy alcohol consumption. Although approximately 20% of alcoholics undergoing liver biopsy reveal histological features of AH, only a minority progress to severe AH with markedly elevated serum liver enzymes, jaundice and impaired liver function. To establish the diagnosis of AH, histology is recommended but not mandatory. Prognostic scores include the Maddrey's discriminant function, the model of end-stage liver disease, the Glasgow Alcoholic Hepatitis score, and the ABIC score. While the former scores identify patients at risk of death or the need for corticosteroids, the response to corticosteroid therapy can be assessed using the Lille model. Treatments include abstinence and enteral nutrition, while pharmacotherapy using corticosteroids either with or without N-acetylcysteine may be indicated for patients with severe AH. Pentoxifylline was found to reduce the risk of hepatorenal syndrome, but data on mortality are limited. Although considered a contraindication in most transplant centers, recent evidence indicates that carefully selected patients with AH could be good candidates for liver transplantation with a prognosis comparable to other indications.


Poggi G.,University of Pavia | Montagna B.,University of Pavia | Di Cesare P.,University of Pavia | Riva G.,University of Pavia | And 3 more authors.
Anticancer Research | Year: 2013

Background: Thermal ablative techniques have gained increasing popularity as safe and effective options for patients with unresectable solid malignancies. Microwave ablation has emerged as a relatively new technique with the promise of larger and faster ablation areas without some of the limitations of radiofrequency thermal ablation. Herein, we report our preliminary results on the feasibility and efficacy of thermal ablation for hepatocellular carcinoma (HCC) with a new 2.45-MHz microwave generator. Patients and Methods: Under ultrasound guidance 194 HCCs in 144 patients were treated through a percutaneous approach. The median diameter of lesions was 2.7 cm (range=2.0-11.0 cm); 68 lesions had a diameter greater than 30 mm. We used a microwave generator (AMICA-GEM, Apparatus for MICrowave Ablation) connected to a 14- or 16-gauge coaxial antenna endowed with a miniaturized sleeve choke to reduce back heating effects and increase the sphericity of the ablated area. Contrast-enhanced computed tomography scan was carried out one month after treatment, and then every three months to assess efficacy. Results: Complete ablation was achieved in 94.3% of the lesions after a mean of 1.03 percutaneous sessions. For small HCCs (diameter <3 cm) complete necrosis was obtained in 100%. Local tumor progressions were found in 10 treated lesions (5.1%) a median of 19.5 months after ablation. Minor complications occurred in 5.1% procedures. No deaths, or other major complications occurred. Conclusion: In our experience, the new device for microwave ablation proved to provide an effective and safe percutaneous ablative method, capable of producing large areas of necrosis.


Lampertico P.,University of Milan | Vigano M.,Hepatology Unit | Colombo M.,University of Milan
Liver International | Year: 2011

Serum HBeAg-negative chronic hepatitis B, which is usually a late stage of chronic hepatitis B virus infection, is difficult to treat, because it is characterized by fluctuating alanine transaminase values resulting in hepatitis flares, accelerated progression to cirrhosis and liver cancer. Antiviral treatment, either long-term nucleot(s)ide therapy or 1-year administration of pegylated interferon (PEG-IFN), is therefore necessary to limit the course of the disease. A sustained virological response to PEG-IFN is achieved in approximately 1/4 of the patients, with significant rates of HBsAg seroclearance. While waiting for the results of several studies whose goal is to improve the long-term efficacy of PEG-IFN, the treatment strategy can be optimized by a careful selection of patients, discontinuation of PEG-IFN as early as possible in primary non-responders and extended therapy (up to 96 weeks) in responders. © 2011 John Wiley & Sons A/S.


Loggi E.,Institute for Research in Biomedicine | Loggi E.,University of Bologna | Gamal N.,University of Bologna | Bihl F.,Hepatology Unit | And 2 more authors.
Journal of Viral Hepatitis | Year: 2014

Hepatitis B virus (HBV) is a major cause of acute and chronic liver inflammation worldwide. The immune response against the virus represents a key factor in determining infection outcome, in terms of both viral clearance and the perpetuation of liver damage. Significant advances have recently been achieved regarding the functions of antiviral CD8+ T cells, leading to a better understanding of their abnormalities during chronic infection as well as the pathways to be manipulated to reverse the immune impairment of chronic infection. In this review, we aimed to analyse the patterns of adaptive immunity that develop during acute infection and the profiles in chronic infection. In addition to CD8+ T cells, which are the best-described subset to date, we reviewed and commented on the direct and indirect roles of CD4+ T cells and B cells. © 2014 John Wiley & Sons Ltd.


Vigano M.,Hepatology Unit | Lampertico P.,University of Milan | Colombo M.,University of Milan
Expert Opinion on Drug Safety | Year: 2011

Several nucleos(t)ide analogs (NUC) are available for the management of patients with chronic hepatitis B (CHB). In most patients, NUC need to be administered on a long-term basis, thus increasing the risk of adverse effects. Adefovir dipivoxil (ADV), the first nucloeotide analog developed to treat CHB, may indeed cause nephrotoxicity. Areas covered: The pharmacokinetic mechanism of action, potential mechanism of renal damage and long-term safety profile of ADV in CHB patients have been reported. The current monitoring modalities, together with dosage adjustments, treatment of patients with ADV-related kidney impairment and the therapeutic algorithm in place at the authors' Liver Center are also summarized. Although, in short-term clinical trials, a daily dose of 10 mg of ADV was safe owing to a low rate of negligible nephrotoxic effects, the same dose may be associated with a usually reversible, proximal renal tubular toxicity as reflected by hypophosphatemia and elevated creatinine levels. Occasionally, Fanconi syndrome occurred in ADV-treated patients. Expert opinion: Renal function at baseline and during treatment should be carefully assessed in all patients receiving ADV to adjust the dose according to creatinine clearance, aimed to prevent or minimize nephrotoxicity. © 2011 Informa UK, Ltd.


Garinis G.A.,University of Catanzaro | Fruci B.,University of Catanzaro | Mazza A.,University of Catanzaro | De Siena M.,Hepatology Unit | And 6 more authors.
International Journal of Obesity | Year: 2010

Objective:We aimed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD).Methods:We carried out a 6-month prospective study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis. In total, 50 patients were enrolled and randomized into two groups: the first group (n25) was given metformin (1 g per day) plus dietary treatment and the second group (n25) was given dietary treatment alone.Results:At the end of the study, the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin (P0.0001) and the diet group (P0.029). Moreover, patient body mass index and waist circumference significantly decreased in both groups (P0.001). Fasting glucose, insulin resistance (evaluated as homeostasis model assessment of insulin resistance (HOMA-IR)) and serum adiponectin decreased in both groups, although these changes reached statistical significance only in the metformin group. In this group, HOMA-IR decreased from 3.31.6 to 2.41.2 (P0.003), whereas it decreased from 3.21.6 to 2.81.1 (not significant, NS) in the diet group. Similarly, the proportion of patients with impaired fasting glucose declined from 35 to 5% (P0.04) in the metformin and from 32 to 12% (NS) in the diet group. At baseline, 40% of patients in both groups met the diagnostic criteria of metabolic syndrome. This proportion decreased to 20% in the metformin group (P0.008) and to 32% in the diet group (NS).Conclusions:In our 6-month prospective study, both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD. However, metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients. © 2010 Macmillan Publishers Limited All rights reserved.


Stickel F.,University of Bern | Stickel F.,Hepatology Unit
Advances in Experimental Medicine and Biology | Year: 2015

Hepatocellular carcinoma shows a rising incidence worldwide, and the largest burden of disease in Western countries derives from patients with alcoholic liver disease (ALD) and cirrhosis, the latter being the premier premalignant factor for HCC. The present chapter addresses key issues including the epidemiology of alcohol-associated HCC, and its link to other coexisting non-alcoholic liver diseases, and additional host and environmental risk factors including the underlying genetics. Also discussed are molecular mechanisms of alcohol-associated liver cancer evolution involving the mediators of alcohol toxicity and carcinogenicity, acetaldehyde and reactive oxygen species, as well as the recently described mutagenic adducts which these mediators form with DNA. Specifically, interference of alcohol with retinoids and cofactors of transmethylation processes are outlined. Information presented in this chapter illustrates that the development of HCC in the context of ALD is multifaceted and suggests several molecular targets for prevention and markers for the screening of risk groups. © Springer International Publishing Switzerland 2015.

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