Hepatitis: Horsmans Y

Robaeys G, Buntinx F, Bottieau E, Bourgeois S, Brenard R, Colle I, De Bie J, Matheï C, Mulkay JP, Van Damme P, Van Ranst M, Verrando R, Michielsen P, Bourgeois N, Brenard R, de Galocsy Ch, Delwaide J, Henrion J, Horsmans Y, Michielsen P, Reynaert H, Robaeys G, Sprengers D, Anonymous00401. · Department of Gastroenterology and Hepatology, Ziekenhuis Oost Limburg, Genk, Schiepse Bos, 6, B-3600 Genk, Belgium. · Acta Gastroenterol Belg. · Pubmed #15832586 No free full text.

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Michielsen P, Brenard R, Bourgeois N, De Galocsy Ch, Delwaide J, Henrion J, Horsmans Y, Nevens F, Reynaert H, Robaeys G, Sprengers D, Van Vlierberghe H, Anonymous00046. · Department of Hepatogastroenterology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem. · Acta Gastroenterol Belg. · Pubmed #12812144 No free full text.

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Horsmans Y. · No affiliation provided · J Hepatol. · Pubmed #15885347 No free full text.

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Horsmans Y. · Service de Gastro-entérologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgique. · Acta Gastroenterol Belg. · Pubmed #10692778 No free full text.

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Marcellin P, Horsmans Y, Nevens F, Grange JD, Bronowicki JP, Vetter D, Purdy S, Garg V, Bengtsson L, McNair L, Alam J. · Hôpital Beaujon, Service d'Hépatologie, 100 Bld du General Leclerc, 92100 Clichy, France. · J Hepatol. · Pubmed #17629590 No free full text.

Abstract: BACKGROUND/AIMS: While combination of peginterferon-alpha (PEG-IFN) and ribavirin (RBV) therapy is the current standard of care for chronic hepatitis C (CHC), only 44-51% of genotype-1 patients achieve a sustained virological response (SVR), and both agents produce treatment-limiting toxicities. In the hepatitis C virus (HCV) replicon system, merimepodib (MMPD), a novel, selective inhibitor of inosine monophosphate dehydrogenase, has shown potent antiviral effects. METHODS: This randomized, placebo-controlled, double-blind study evaluated the safety and antiviral activity of PEG-IFN-alpha2b and RBV combined with either placebo, 25mg MMPD every 12h (q12h), or 50mg MMPD q12h in interferon-alpha (IFN) and RBV nonresponders. After 24 weeks of treatment, subjects with undetectable HCV RNA were proposed to continue assigned treatment for up to 24 additional weeks. RESULTS: The PEG-IFN-alpha, RBV, and MMPD combination was well tolerated at both doses. After 24 weeks, the proportion of HCV RNA undetectable subjects was 8/11 (73%) in the 50-mg MMPD group, 2/10 (20%) in the 25-mg MMPD group, and 3/10 (30%) in the placebo group (P=0.02, Jonckheere-Terpstra test for increasing dose response). Ten subjects entered and completed an extension study, at Week 48, 2 of 2 (100%) of the 25-mg and 3 of 5 (60%) of the 50-mg subjects remained HCV RNA undetectable, compared with 3 of 3 (100%) of the placebo subjects. At Follow-up Week 24, 2 (100%) of the 25-mg , and 1 (25%) of the 50-mg subjects remained undetectable, compared with 1 (33%) of the placebo subjects. Pharmacokinetic and pharmacodynamic analyses showed a correlation between MMPD exposure and early virological response at week 12, but not with hemoglobin decreases often associated with RBV. CONCLUSIONS: In conclusion, PEG-IFN-alpha2b and RBV combined with 50 mg MMPD q12h was well tolerated and induced virological response with undetectable HCV RNA in IFN-alpha and RBV nonresponders.

Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J. · Clinic of Internal Medicine II, Department of Medicine, Saarland University Hospital, Kirrbergerstrasse, 66421 Homburg/Saar, Germany. · J Hepatol. · Pubmed #16290907 No free full text.

Abstract: BACKGROUND/AIMS: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-1 (n=235) and a screening viremia < or =600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958-65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%). CONCLUSIONS: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates.

Horsmans Y, Berg T, Desager JP, Mueller T, Schott E, Fletcher SP, Steffy KR, Bauman LA, Kerr BM, Averett DR. · Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Unit de Pharmacologie Clinique, Brussels, Belgium. · Hepatology. · Pubmed #16116638 No free full text.

Abstract: Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P = .001) reduction of plasma HCV RNA (mean, -0.76; range, -2.85 to +0.21 log(10) units) in otherwise untreated patients (n = 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2'-, 5'- oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects.

Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM. · Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université Catholique de Louvain, Brussels, Belgium. · Eur J Clin Nutr. · Pubmed #15770222 No free full text.

Abstract: OBJECTIVE: In experimental animals, recent results suggest that the addition of inulin-type fructans such as oligofructose (OFS) in the diet decreases triacylglycerol accumulation in the liver tissue. Therefore, we have investigated the effect of daily ingestion of OFS in seven patients with nonalcoholic steatohepatitis (NASH), confirmed by liver biopsies. DESIGN: They received 16 g/day OFS or maltodextrine (placebo) for 8 weeks in a randomized double-blind crossover design. Energy intake, body composition, liver steatosis and blood parameters were analysed after 4 and 8 weeks of dietary supplementation. RESULTS: Compared to placebo, OFS decreased significantly serum aminotransferases, aspartate aminotransferase after 8 weeks, and insulin level after 4 weeks, but this could not be related to significant effect on plasma lipids. CONCLUSION: This pilot study supports the putative interest of OFS in the management of liver diseases associated with abnormal lipid accumulation in humans.

Van Vlierberghe H, Leroux-Roels G, Adler M, Bourgeois N, Nevens F, Horsmans Y, Brouwer J, Colle I, Delwaide J, Brenard R, Bastens B, Henrion J, de Vries RA, de Galocsy C, Michielsen P, Robaeys G, Bruckers L. · Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium. hans.vanvlierberghe@rug,ac.be · J Viral Hepat. · Pubmed #14633181 No free full text.

Abstract: The standard treatment for patients with chronic hepatitis C is a 6-12-month combination therapy with interferon alpha and ribavirin. Induction treatment could result in a faster early decline of the hepatitis C virus (HCV) load and a better response rate. Naive chronically infected HCV patients (n = 454) were randomized into two arms to receive either induction treatment with interferon alpha 2b 5 million units (MU) subcutaneously (s.c.) daily during a period of 8 weeks (arm A); or treatment with interferon alpha 2b 5 MU s.c. three times a week (TIW) for a period of 8 weeks (arm B). After week 8, interferon treatment in both arms was 3 MU s.c. TIW for a total period of 12 months. In both arms, ribavirin (1000-1200 mg orally per day) was added at week 4. Induction treatment resulted in a higher virological response at week 8 of treatment (66%vs 47%; P < 0.01). However, response at the end of treatment and at 6 months follow-up was not different (53%vs 50%, 41%vs 33%). The occurrence of adverse events and the drop-out rate were similar in both arms. Although an early virological response is observed more frequently in the induction treatment, end of treatment response and sustained responses did not differ.

Nevens F, Roskams T, Van Vlierberghe H, Horsmans Y, Sprengers D, Elewaut A, Desmet V, Leroux-Roels G, Quinaux E, Depla E, Dincq S, Vander Stichele C, Maertens G, Hulstaert F. · Department of Hepatology, UZ Gasthuisberg, Belgium. · Hepatology. · Pubmed #14578869 No free full text.

Abstract: New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty-five chronic hepatitis C patients (genotype 1) were randomized to receive 20 mug of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty-four patients (12 men, 12 women; mean age, 52 y; 18 interferon-based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV-RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1-specific T-cell response. The increase in anti-E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P < or =.01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study.

Horsmans Y, Collez I, Van Vlierberghe H, Langlet P, Adler M, Bourgeois N, Brenard R, Michielsen P, Goossens A, Bruckers L, Anonymous00024. · Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. · Acta Gastroenterol Belg. · Pubmed #19198574 No free full text.

Abstract: BACKGROUND AND STUDY AIMS: The combination of Pegylated (PEG)interferon alpha-2b and ribavirin is considered to be the standard treatment for naïve chronic hepatitis C patients. Study aims are to evaluate the differences between standard interferon and PEG-interferon by conducting a multi-centre, controlled randomized trial comparing 3 groups. Group A : daily interferon alfa-2b at a dose of 4 MIU + ribavirin, Group B : PEG-interferon alfa-2b at a dose of 100 mcg/week + ribavirin; Group C: interferon alfa-2b at a dose of 3 MIU TIW + ribavirin PATIENTS AND METHODS: Multicentrer, open label study including naïve chronic Hepatitis C Virus patients randomised in three groups with a ratio of 2:2:1. Group A: daily interferon alpha-2b (4 MIU s.c. for patients > 65 kg or 0.06 MIU/kg < 65 kg) and ribavirin, group B: PEG-interferon alpha-2b (100 microg s.c. weekly for patients > 65 kg or 1.5 microg/kg weekly for patients < 65 kg) and ribavirin and group C (reference arm) : interferon alpha-2b (3MIU s.c. TWI) and ribavirin. The duration of the treatment was 48 weeks for all 3 groups, with a 6 month follow-up period. 336 patients were enrolled in the study and included in the intention-to-treat analysis; 78 never started treatment (35 in group A, 28 in group B and 15 in group C): 101 in group A, 98 in group B and 59 in group C. RESULTS: Demographic data, PCR results and reasons for early withdrawal have been statistically analysed. At baseline, the 3 groups did not show any statistical difference regarding age, gender, race, genotypes and METAVIR score. At week 24 on treatment, HCV ribonucleic acid RNA was undetectable in 87% in group A, in 79% in group B and in 69% in group C. At the end of treatment, 73% 74% and 58% respectively, had a negative PCR result. At week 24 of follow-up, these results were 71%, 64% and 48%, respectively. When comparing the efficacy of the daily interferon (+ ribavirin) and the PEG-interferon (+ ribavirin) regimen, no statistical difference was found (p = 0.32). In group A, 38% of drop-outs were due to adverse events compared to 37% in group B and 58% in group C. No statistical differences were observed regarding safety. CONCLUSION: Daily weight based interferon alpha-2b dosing and PEG interferon alpha-2b weighed based dosing once weekly both in combination with Ribavirin offer the same efficacy and safety rates.

Vandepapelière P, Horsmans Y, Moris P, Van Mechelen M, Janssens M, Koutsoukos M, Van Belle P, Clement F, Hanon E, Wettendorff M, Garçon N, Leroux-Roels G. · GlaxoSmithKline Biologicals, 89 rue de l'Institut, 1330 Rixensart, Belgium. · Vaccine. · Pubmed #18272264 No free full text.

Abstract: A randomised, double-blind study assessing the potential of four adjuvants in combination with recombinant hepatitis B surface antigen has been conducted to evaluate humoral and cell-mediated immune responses in healthy adults after three vaccine doses at months 0, 1 and 10. Three Adjuvant Systems (AS) contained 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21, formulated either with an oil-in-water emulsion (AS02B and AS02V) or with liposomes (AS01B). The fourth adjuvant was CpG oligonucleotide. High levels of antibodies were induced by all adjuvants, whereas cell-mediated immune responses, including cytolytic T cells and strong and persistent CD4(+) T cell response were mainly observed with the three MPL/QS21-containing Adjuvant Systems. The CD4(+) T cell response was characterised in vitro by vigorous lymphoproliferation, high IFN-gamma and moderate IL-5 production. Antigen-specific T cell immune response was further confirmed ex vivo by detection of IL-2- and IFN-gamma-producing CD4(+) T cells, and in vivo by measuring increased levels of IFN-gamma in the serum and delayed-type hypersensitivity (DTH) responses. The CpG adjuvanted vaccine induced consistently lower immune responses for all parameters. All vaccine adjuvants were shown to be safe with acceptable reactogenicity profiles. The majority of subjects reported local reactions at the injection site after vaccination while general reactions were recorded less frequently. No vaccine-related serious adverse event was reported. Importantly, no increase in markers of auto-immunity and allergy was detected over the whole study course. In conclusion, the Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be fundamental to develop effective prophylactic vaccines against complex pathogens, e.g. malaria, HIV infection and tuberculosis, and for special target populations such as subjects with an impaired immune response, due to age or medical conditions.

Vandepapelière P, Lau GK, Leroux-Roels G, Horsmans Y, Gane E, Tawandee T, Merican MI, Win KM, Trepo C, Cooksley G, Wettendorff M, Ferrari C, Anonymous00441. · GlaxoSmithKline Biologicals, 1330 Rixensart, Belgium. · Vaccine. · Pubmed #18031872 No free full text.

Abstract: Induction of curative immune responses by therapeutic vaccination in chronic viral infections such as chronic hepatitis B (CHB) is expected to be facilitated by reduction of viral load by antiviral treatment. In this open label, controlled, randomized study, 195 patients with HBeAg positive CHB were randomized to receive 12 doses of HBsAg with AS02B adjuvant candidate vaccine plus lamivudine daily for 52 weeks or lamivudine daily alone. The combined administration of vaccine and lamivudine was safe and well tolerated, but did not improve the HBe seroconversion rate (18.8%) when compared to treatment with lamivudine alone (16.1%) (p=0.6824). Despite induction of a vigorous HBsAg-specific lymphoproliferative response, cytokine production and anti-HBs antibodies, therapeutic vaccination with an adjuvanted HBsAg vaccine administered concomitantly with lamivudine did not demonstrate superior clinical efficacy in HBeAg positive CHB patients as compared to lamivudine therapy alone.

Borbath I, Leclercq IA, Abarca-Quinones J, Desaeger C, Lebrun V, Moulin P, Sempoux C, Horsmans Y. · Gastroenterology Laboratory, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate, 10, Brussels 1200, Belgium. · Cancer Sci. · Pubmed #17900309 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its incidence is increasing worldwide. Due to the known risk factors (mainly hepatitis B and C viruses), we believe there is a rationale for a chemopreventive approach to treat HCC. Here, based on described in vitro data, we evaluated the preventive effects of lanreotide, a somatostatin analog, on the induction of early carcinogenic events. We monitored preneoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in male Wistar rats, using diethylnitrosamine and 2-acetylaminofluorene. Lanreotide was given starting the day after the first diethylnitrosamine injection. By quantitative morphometry, we showed that lanreotide significantly decreases the size of induced preneoplastic foci. Analysis of proliferation and apoptosis assessed by immunohistochemistry, showed decreased proliferation and increased cell death in rats treated with lanreotide. As these events were associated with a significant decreased expression of the cell cycle regulator cyclin D1 and an increased expression of the cyclin-dependent kinase inhibitor p27(kip1) compared to the non-treated group, it is tempting to speculate that these factors are involved in the favorable effect of lanreotide. In conclusion, lanreotide significantly decreases early carcinogenic transformation in a two-step rat model. As lanreotide has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC.

Gerkens S, Nechelput M, Annemans L, Peraux B, Beguin C, Horsmans Y. · Université catholique de Louvain, Cliniques universitaires Saint-Luc, Bruxelles, Belgium. · Acta Gastroenterol Belg. · Pubmed #17715631 No free full text.

Abstract: BACKGROUND AND STUDY AIMS: The treatment of patients with moderate chronic hepatitis C and persistently normal alanine aminotransferase levels is still under discussion and the cost-effectiveness of such strategy is unknown. The objective of this study was to estimate the cost-effectiveness of their treatment in comparison with no treatment. PATIENTS AND METHODS: The assessed treatment is composed of pegylated interferon alpha-2a and ribavirin, which is the current standard treatment. Two groups were studied: patients with genotype 1 and patients with genotypes 2-3. At the beginning of the study, patients were aged of 45. Long-term economic and clinical outcomes over a 30 year period were predicted using a Markov simulation model. A health care payer perspective was chosen. Data were obtained from published literature. Variations of uncertainty parameters were assessed through a sensitivity analysis. RESULTS: The incremental cost-effectiveness ratios (ICERs) were Euro 5,338/QALY for genotype 1 and Euro 1,080/QALY for genotypes 2-3. In the sensitivity analysis, ratios remained lower than Euro 20,000. A Monte Carlo simulation with 1,000 iterations gives a 95% confidence interval for the ICER of Euro 3,199 to Euro 8,972 for genotype 1 and Euro 56 to Euro 1,981 for genotypes 2-3. CONCLUSION: Even though the treatment of these patients generates a cost, it has the advantage that in comparison with no treatment, a great number of people are cured, complications are less frequent and patients gain more quality-adjusted life-year (QALY), which involves an ICER considered as acceptable for the European society (< Euro 20,000).

Gerkens S, Nechelput M, Annemans L, Peraux B, Mouchart M, Beguin C, Horsmans Y. · Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels, Belgium. · J Viral Hepat. · Pubmed #17650286 No free full text.

Abstract: According to the current guidelines, it is advised not to treat patients with mild chronic hepatitis C. However, discussions as to giving immediately a treatment (direct treatment) to these patients have started and the incremental cost-effectiveness ratio (ICER) of such strategy is still unknown. The aim of this study was to estimate, in the health care payer perspective, the ICER of a direct treatment of patients with mild chronic hepatitis C in comparison with the strategy of monitoring these patients and treat them when the disease will progress to the state of moderate chronic hepatitis. The treatment assessed was the current standard treatment composed of pegylated interferon alpha-2a and ribavirin. At the beginning of the study, patients were aged 45. Long-term economic and clinical outcomes over a 30-year period were predicted using a Markov simulation model. Data were obtained from published literature. Monte Carlo simulations were used to determine 95% confidence intervals of results. The ICER of a direct treatment with PEG IFN alpha-2a and ribavirin is 23,046 euro/QALY (CI 95% 3,882 euro-42,392 euro) for genotypes 1-4-5-6 and 4,631 euro/QALY (CI 95% 797 euro-7,881 euro) for genotypes 2-3. Sensitivity analysis shows that it is only in extreme circumstances related to the utilities that the ICER for genotypes 1-4-5-6 is unacceptably high for the society (>50,000 euro). Even though a direct treatment is more expensive, it gives the advantage of curing greater number of patients and of increasing quality-adjusted life-years (QALYs), implying that such strategy is generally cost-effective at a threshold of 50,000 euro/QALY.

Stärkel P, Saeger CD, Leclercq I, Horsmans Y. · Department and Laboratory of Gastroenterology, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. · Lab Invest. · Pubmed #17318196 links to  free full text

Abstract: In vitro and animal data suggest that hepatitis C virus (HCV) proteins might interfere with signal transducer and activator of transcription 3 (Stat3) signaling. It remains unknown whether Stat3 influences the apoptotic-proliferation balance and how this may relate to liver fibrosis progression in HCV-infected patients. We assessed Stat3 expression and DNA-binding as well as expression of its regulators protein inhibitor of activated Stat 3 (Pias3) and suppressor of cytokine signaling 3 (Socs3) in 65 HCV-infected livers at various stages of fibrosis progression. We then determined the level of expression of the proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) in conjunction with pro- and antiapoptotic markers Bax and Bcl-2 in the same liver samples. With the onset of fibrosis, Stat3 DNA-binding decreased and became almost undetectable in livers with bridging fibrosis or cirrhosis. Stat3 DNA-binding inversely correlated with Pias3 expression and Stat3-Pias3 interaction increased with the progression of fibrosis. Cyclin D1 and PCNA in hepatocytes decreased dramatically during fibrosis progression and levels highly correlated with Stat3 expression. In addition, an antiapoptotic profile due to upregulation of Bcl-2 principally in infiltrating inflammatory cells was observed with progressing fibrosis. In conclusion, fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3-Stat3. The decrease in Stat3 activity correlated with reduced hepatocytes proliferation and a positive antiapoptotic balance in infiltrating inflammatory cells that are known mediators of cell damage in HCV.

Horsmans Y. · Department of Gastroenterology, Cliniques Universitaires Saint-Luc Université Catholique de Louvain, Belgium. · J Antimicrob Chemother. · Pubmed #16951413 links to  free full text

Abstract: Since the success rate of the antiviral treatment of chronic hepatitis C (HCV) is increasing, the knowledge of side effects due to this therapy must also improve. Among these side effects, depression and other neuro-psychiatric symptoms are among the most important. It must be outlined that conditions may exist before treatment in relation to the viral infection. However, pegylated interferon (IFN) administration is associated with a huge increase in the importance and the incidence of neuro-psychiatric symptoms. This has led several experts to claim that antiviral therapy should not be given to HCV patients having psychiatric contraindications. This last assertion seems to be disproved on the basis of results of recent clinical trials using selective serotonin reuptake inhibitors (SSRI). Pathogenesis of these neuro-psychiatric symptoms, however, remains unknown although the impact of IFN on glucocorticoid receptors and on serotonin 1A receptors is privileged. In conclusion, advances in HCV antiviral therapy and the comprehension and subsequent treatment of side effects induced by this therapy should allow us to treat more patients with greater success.

Kanaan N, Horsmans Y, Goffin E. · Department of Nephrology, Université catholique de Louvain, Cliniques Universitaires St. Luc, Brussels, Belgium. · Clin Nephrol. · Pubmed #16550752 No free full text.

Abstract: A 57-year-old man presented with nephrotic syndrome associated with active HBV infection. Liver biopsy showed severe portal and moderate lobular inflammation, patchy necrosis, moderate fibrosis and several "ground glass" cells. Immunofluorescence microscopical view of the renal biopsy showed diffuse granular IgG deposits along the glomerular basement membrane, compatible with MN. As symptomatic therapy with ACE inhibitors did not improve the nephrotic syndrome, lamivudine 100 mg o.d. was initiated. HBV-DNA became undetectable after 10 weeks and seroconversion of HBeAg and HBsAg to anti-HBe and anti-HBs occurred after 2 additional months; proteinuria normalized subsequently. This observation documents for the first time in an adult the beneficial effect of lamivudine in glomerulonephritis related to HBV infection with HBV seroconversion and complete remission of the nephrotic syndrome.

Stärkel P, Stoffel M, Lerut J, Horsmans Y. · Department of Gastroenterology, St. Luc University Hospital, Brussels, Belgium. · Liver Transpl. · Pubmed #16184571 links to  free full text

Abstract: Strategies using lamivudine and hepatitis B immunoglobulins (HBIg) for prevention of hepatitis B virus (HBV) reinfection after liver transplantation (LT) are expensive since life-long treatment is needed. We evaluated the possibility to obtain protective hepatitis B surface antigen (HBsAg) antibody (anti-HBs) titers after LT and to discontinue HBIg prophylaxis after a reinforced course of vaccination against HBV using an experimental adjuvant HBsAg / AS04 vaccine (GlaxoSmithKline Biologicals [GSK], Rixensart, Belgium) in patients transplanted for hepatitis B. Fifteen LT patients on stable low-level immunosuppression were vaccinated with a double dose of the vaccine at 0, 1, 2, 6, and 12 months: 5 patients were transplanted for nonviral diseases and 10 patients were transplanted for HBV on HBIg monotherapy. HBIg were continued during baseline vaccination (0, 1, and 2 months) and when anti-HBs titers determined every 6 weeks dropped below 150 IU/L. Overall follow-up was 18 months. Sustained long-term response to vaccination was defined as anti-HBs titers >500 IU/L without further need for HBIg administration during a follow-up period of at least 12 months. Overall sustained response to vaccination was 53% (8 / 15 patients); 80% (4 / 5 patients) in the nonviral disease group and 40% (4 / 10 patients) in the HBV group (2 /2 fulminant and 2/8 chronically infected patients) developed a sustained long-term response and were completely free of HBIg at the end of the 18-month follow-up. No HBV recurrence, rejection episodes, or side effects occurred during the follow-up. In conclusion, protective anti-HBs titers were obtained in a substantial number of LT patients following a reinforced course of HBV vaccination with vaccines containing new immunostimulating adjuvants. Vaccination seems well tolerated and safe and allows long-term discontinuation of HBIg.

Stärkel P, De Saeger C, Leclercq I, Strain A, Horsmans Y. · Department and Laboratory of Gastroenterology, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. · J Hepatol. · Pubmed #16098628 No free full text.

Abstract: BACKGROUND/AIMS: In vitro and animal data suggest that alcohol and hepatitis C virus (HCV) proteins might interfere with Stat3 signaling, a potential regulator of liver cell apoptosis and proliferation. METHODS: We assessed Stat3 expression, activity and the apoptotic-proliferation balance in end-stage HCV and alcoholic liver disease (ALD) in man. Explanted livers of HCV and ALD patients were compared to normal and primary biliary cirrhosis (PBC) livers. RESULTS: Although Stat3 expression and phosphorylation was not altered in HCV and ALD cirrhosis, Stat3 DNA-binding was not detected in all ALD and most HCV samples. Deficient Stat3 DNA-binding was associated with high Pias3 expression, but not with increased Socs3 levels. Bcl-2 was up-regulated in HCV and ALD together with decreased Caspase3 activity. Compared to base-line cell proliferation in normal donor livers, HCV cirrhosis showed a marked reduction in cyclin D1 and PCNA, whereas both markers were only slightly reduced in ALD. CONCLUSIONS: End-stage HCV and ALD cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. Therefore, impaired activation of Stat3 target genes might contribute to disturbed liver regeneration and repair. The attempt in cirrhotic livers to favor anti-apoptotic over pro-apoptotic pathways is not sufficient to compensate for the low cellular proliferation rates.

Hutse V, Verhaegen E, De Cock L, Quoilin S, Vandenberghe H, Horsmans Y, Michielsen P, Van Damme P, Van Vlierberghe H, Claeys F, Vranckx R, Van Oyen H. · Unit of Epidemiology, Scientific Institute of Public Health, Brussels, Belgium. · J Med Virol. · Pubmed #16032713 No free full text.

Abstract: Currently viral antigens and antibodies are detected by traditional serological tests. However, the introduction of oral fluid as an alternative medium would allow other alternatives. The collection of oral fluid is, in comparison with venepuncture, less invasive, less painful, less expensive (i.e., no trained personal required), and safe (prevention of needle stick injuries). Also large numbers of samples can be collected easily for epidemiological purposes. Forty-three HBsAg positive and seventy-three HBsAg negative paired serum/oral fluid samples were tested. They were collected from patients attending university hospitals. The oral fluid samples were collected using the Oracol collection device and they were subjected to an IgG quantification assay to ensure their quality and quantity. The detection of HBsAg in oral fluid was carried out using a modified ETI-MAK-4 ELISA. The validation of this oral fluid test gave a sensitivity and specificity of 90.7% and 100%, respectively. The modified ETI-MAK-4 ELISA is a suitable test for oral fluid samples collected by the Oracol collection device for epidemiological purposes.

Haufroid V, Ligocka D, Wallemacq P, Lison D, Horsmans Y. · Industrial and Environmental Toxicology Unit, Université catholique de Louvain, Clos Chapelle-aux-Champs 30/54, B-1200, St. Luc Hospital, Brussels B-1200, Belgium. · Toxicol Lett. · Pubmed #15585372 No free full text.

Abstract: The induction of cytochrome P4502E1 (CYP2E1) is believed to play a role in the development of fibrosis in hepatitis C patients. However, information about CYP2E1 activity in chronic hepatitis C patients is fragmentary and the relationship between CYP2E1 activity and mRNA expression is unknown in this disease. The purpose of this study was (a) to characterise CYP2E1 activity in those patients and (b) to analyse its relationship with CYP2E1 mRNA expression in the liver and in peripheral blood lymphocytes (PBLs), previously proposed as a surrogate to assess changes in CYP2E1 activity. Fourteen chronic hepatitis C patients were submitted to a routine transcutaneous liver biopsy. CYP2E1 activity was assessed by using chlorzoxazone (CZX) pharmacokinetic parameters and hepatic and PBLs CYP2E1 mRNA expression was measured by real-time RT-PCR. The mean oral clearance of CZX (CLT: 21.5+/-10.1L/h) was within the normal range and the chlorzoxazone metabolic ratio (CMR) at t = 2 h was closely related to other CZX pharmacokinetic parameters. None of the pharmacokinetic parameters did significantly correlate with CYP2E1 mRNA, neither in the liver nor in PBLs. Furthermore, there was no significant relationship between CYP2E1 mRNA levels in paired liver and PBL samples. Our data indicate that early stages of chronic hepatitis C are not associated with CYP2E1 induction. In this disease, the determination of the CMR at t = 2 h represents a reliable index to assess CYP2E1 activity. The measurement of CYP2E1 expression, at the mRNA level, in PBLs or in liver is not useful for that purpose.

Leclercq IA, Farrell GC, Sempoux C, dela Peña A, Horsmans Y. · Gastroenterology Unit, Université Catholique de Louvain (UCL), GAEN/UCL 53/79, Avenue E. Mounier, 53, B-1200 Brussels, Belgium. · J Hepatol. · Pubmed #15582125 No free full text.

Abstract: BACKGROUND/AIMS: While oxidative stress is a feature of non-alcoholic steatohepatitis, the causal link between oxidative stress and inflammatory recruitment has yet to be demonstrated. We analysed the role of NF-kappaB redox-sensitive signalling pathway of inflammatory recruitment in experimental steatohepatitis. METHODS: Mice were fed the methionine and choline deficient (MCD) or the control diet, with or without curcumin, an NF-kappaB inhibitor, for up to 4 weeks. Histopathology, lipoperoxides, NF-kappaB/DNA binding and expression of NF-kappaB-regulated genes were assessed. RESULTS: MCD-fed mice developed steatohepatitis accompanied by dramatic accumulation of hepatic lipoperoxides, activation of NF-kappaB and induction of pro-inflammatory ICAM-1, COX-2, MCP-1 and CINC mRNA. Curcumin significantly reduced MCD-induced inflammation but had no effect on steatosis or on the level of hepatic lipid peroxides. Curcumin prevented the MCD-induced activation of NF-kappaB and decreased downstream induction of ICAM-1, COX-2 and MCP-1. However, it failed to reduce activation of AP-1, MAPK pathways or CINC expression. CONCLUSIONS: Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Annet L, Materne R, Danse E, Jamart J, Horsmans Y, Van Beers BE. · Department of Radiology, Université Catholique de Louvain, St-Luc University Hospital, Avenue Hippocrate 10, B-1200 Brussels, Belgium. · Radiology. · Pubmed #12970464 links to  free full text

Abstract: PURPOSE: To determine the correlations between hemodynamic parameters of hepatic flow measured with magnetic resonance (MR) imaging and Doppler ultrasonography (US) and the severity of cirrhosis and portal hypertension. MATERIALS AND METHODS: Forty-six patients referred for measurements of portal venous pressure (three with normal liver, 12 with chronic hepatitis, and 31 with cirrhosis [10 with Child-Pugh class A cirrhosis; 13 with class B cirrhosis; and eight with class C cirrhosis]) were included in the study. Apparent liver perfusion, apparent arterial and portal perfusion, portal fraction, distribution volume, and mean transit time were measured with dynamic contrast material-enhanced MR imaging. Portal velocity, portal flow, congestion index, right hepatic artery resistance index, and modified hepatic index were measured with Doppler US. Results in patients with cirrhosis and those without cirrhosis were compared with the Wilcoxon rank sum test. Correlations were assessed with Spearman rank correlation coefficients. RESULTS: With MR imaging, all flow parameters except distribution volume were significantly different between patients with and those without cirrhosis (P <.05). There was a significant correlation between all flow parameters measured with MR imaging and portal pressure (P <.02). Apparent arterial (P =.024) and portal (P <.001) perfusion, portal fraction (P <.001), and mean transit time (P =.004) were correlated with Child-Pugh class. Flow parameters measured with Doppler US did not differ significantly between patients with and those without cirrhosis. Only right hepatic arterial resistance (P <.007) and portal flow (P <.043) were weakly (r < 0.7) correlated with portal pressure. No Doppler US parameter was correlated with Child-Pugh class. CONCLUSION: Hepatic flow parameters measured with MR imaging correlate with the severity of cirrhosis and portal hypertension. Doppler US parameters are only weakly correlated with portal pressure.