Judit Gervain

Cytokine (IL-10, IL-28B and LT-A) gene polymorphisms in chronic hepatitis C virus infection

Abstract Background Since the clearance of hepatitis C virus (HCV) infection depends on the cytokines which are under genetic control, we have studied genetic polymorphisms of two pro-inflammatory interleukin-28B (IL-28B) (also named as interferon λ-3) and lymphotoxin-A (LT-A) as well as of one anti-inflammatory cytokine interleukin-10 (IL-10) genes in patients with HCV infection. We examined the allele frequencies of these genes in HCV patients as compared with healthy controls, and determined their association with sustained virological response (SVR) on PEG-IFN α-2a + ribavirin (RBV) (P/R) treatment, to assess the predictive value of these genetic variants. A total of 292 chronic HCV genotype 1 infected patients and 104 healthy controls have been studied. The samples were genotyped using PCR-RFLP and ABI Taqman genotyping assay. Results IL-28B — The C/C genotype in HCV patients occurred with lower frequency than in healthy controls (28.11% vs. 51.92%, p = 0.0001, OD 2.76), suggesting a protective role ...

Serum Anti-cholesterol Antibodies in Chronic Hepatitis-C Patients During IFN-α-2b Treatment

Previously we detected more than 3 times higher anti-cholesterol antibody (ACHA) levels in HIV positive patients compared to healthy individuals, however, this level significantly decreased during highly active anti-retroviral therapy (HAART). In our present study we examined whether these findings could also be detected in patients with chronic hepatitis C (CHC). We calculated the correlation between the ACHA levels and the C5b-9 complement activation product. 39 patients with CHC were treated with IFN-alpha-2b (Schering-Plough) 5 MU daily for 6 weeks, followed by 5 MU TIW. Serum levels of ACHA and complement activation products were measured with ELISA. Serum HCV RNA was measured by a highly sensitive branched DNA technique before and 3, 6 and 12 months after the beginning of IFN-alpha-2b therapy. 52 healthy persons served as controls. At the onset of treatment ACHA level was significantly (p = 0.0062) higher in patients (40 (24-69) AU/ml) (median (interquartile range)) than in control sera (26 (20-35) AU/ml). In the 26 responder patients ACHA levels decreased to the normal level during the therapy, but no change was observed in the 13 non-responders. In patients with a sustained response ACHA levels remained low till the end of the 12 months IFN treatment. ACHA levels were significantly (p = 0.0422) higher in the patients with low ( or = 4.0 mmol/l) cholesterol concentrations. The ACHA level before the therapy strongly correlated (r = 0.5499, p = 0.0014) with C5b-9 serum levels. ACHA levels are elevated in CHC, but this elevation is not as high as in HIV. Decrease of viral load by IFN-alpha-2b treatment in the responders results in normalization of ACHA concentration. High ACHA levels in patients with low serum cholesterol concentration suggest that high ACHA levels may contribute to the decrease in cholesterol levels. The correlation between the ACHA and C5b-9 levels indicate, that the ACHA may play a role in the complement activation in CHC.

IL28B and IL10R −1087 polymorphisms are protective for chronic genotype 1 HCV infection and predictors of response to interferon-based therapy in an East-Central European cohort

BackgroundPrevious studies have shown that single nucleotide polymorphisms (SNP) in IL28B and IL10R are associated with sustained virological response (SVR) in chronic hepatitis C patients treated with pegilated interferon plus ribavirin (P/R). The present study extends our earlier investigations on a large East-Central European cohort. The allele frequencies of IL28B and IL10R in genotype 1 HCV infection were compared with that of healthy controls for the purpose of examining the relationship between the polymorphisms and the SVR to P/R treatment.MethodsA total of 748 chronic HCV1 infected patients (365 male, 383 female; 18–82 years) and 105 voluntary blood donors as controls were enrolled. Four hundred and twenty HCV patients were treated with P/R for 24–72 weeks, out of them 195 (46.4%) achieved SVR. The IL28 rs12979860 SNP was determined using Custom Taqman SNP Genotyping Assays. The IL10R −1087 (also known as IL10R −1082 (rs1800896) promoter region SNP was determined by RT-PCR and restriction fragment length polymorphism analysis.ResultsThe IL28B CC genotype occurred with lower frequency in HCV patients than in controls (26.1% vs 51.4%, p<0.001). P/R treated patients with the IL28B CC genotype achieved higher SVR rate, as compared to patients with CT (58.6% vs 40.8%, p=0.002). The prevalence of IL10R −1087 GG genotype was lower in patients than in controls (31.8 % vs 52.2%, p<0.001). Among patients achieving SVR, the IL10R −1087 GG genotype occurred with higher frequency than the AA (32.0% vs 17.4%, p=0.013). The IL28B T allele plus IL10R A allele combination was found with higher prevalence in patients than in controls (52% vs 20.7%, p<0.001). The IL28B CC plus IL10R A allele combination occurred with higher frequency among patients with SVR than in non-responders (21.3% vs 12.8%, p=0.026). Both the IL28B CC plus IL10R GG and the IL28B CC plus IL10R A allele combinations occurred with lower frequency in patients than in controls.ConclusionsIn our HCV1 patients, both the IL28B CC and IL10R GG genotypes are associated with clearance of HCV. Moreover, distinct IL28B and IL10R allele combinations appear to be protective against chronic HCV1 infection and predictors of response to P/R therapy.

Symptoms of hepatocellular carcinoma. Laboratory tests used for its diagnosis and screening

Early stage hepatocellular carcinoma is a symptom-free disease. Local and general symptoms occur due to the growth of the tumor tissue and the infiltration of the surrounding blood vessels. Illness progression is indicated by the development of abdominal discomfort, cachexia, therapy-resistant decompensation of previously compensated cirrhosis and in severe cases, the thrombosis of the portal vein or the hepatic veins. Characteristic laboratory findings are the quickly deteriorating blood and liver function tests results, the occurrence of haemostatic disorders and occasional hypoglycemia and/or hypercalcemia. To clarify the etiology and to identify high risk patients, we need to differentiate alcohol-, drug- or chemical-induced hepatic disorders, viral hepatitis B, C and Delta, metabolic disorders and non-alcoholic steatohepatitis. In the case of focal hepatic lesions, persistently elevated alfa fetoprotein levels have a high diagnostic value. At levels over 200 ng/ml, the positive predictive value is >90%. Other, less commonly measured biomarkers are the glycosilated alfa fetoprotein-L3 and the vitamin K-deficiency induced des-gamma-carboxy prothrombin. The risk of tumor occurrence is multiple in patients with HbeAg positive chronic hepatitis B if the virus is of genotype C with mutations in the 1762 and 1764 locations of the core promoter region. Abdominal ultrasound and measurement of alfa fetoprotein is recommended every 6 months for high risk individuals, or every 3-4 months over an 18-24 months period for patients with hepatic lesions of <1cm and of unknown malignancy.

Significance of the changes in HBV DNA and HBsAg levels during the treatment of chronic hepatitis B

With the development of new drugs, there has been a significant progression in the treatment of viral hepatitis B over the past five years. Based on their effect mechanisms, the currently available seven different drugs can be classified either as those of the interferon group or those of the nucleoside analogue group. Despite the pharmacological advances, it is still rare to achieve sustained response. The chances of a long-term inactive hepatitis stage, however, have greatly increased with the growing opportunities for personalized pharmacological treatment based on the selection of the correct type of drug, the timely modification of therapy in case of ineffectiveness and the determination of the optimal time and length of the therapy. For this, it is necessary to monitor several predictive, non-invasive biomarkers. For the initiation of the therapy, the most important markers are HBeAg, alanine-aminotranferase and HBV DNA serum levels and the viral genotype. During therapy, quantitative monitoring of the HBV DNA and HbsAg levels helps most to differentiate between those who will respond fast, those who will need longer treatment and those who are unlikely to respond and therefore need alternative drug therapy. A rapid decrease in or disappearance of HBsAg is predictive of successful response during interferon therapy, while changes in the HBV DNA level are more informative during treatment with nucleoside analogues. It is expected that information on the effects of combination therapy will become available soon and this may alter both the currently recommended treatment and monitoring strategy.

Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy

Aim of the study Combination of ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3DDA±RBV) therapy is shown to be effective in HCV genotype 1 (GT1) infected patients. However, sparse data exist in patients who failed previous boceprevir or telaprevir based therapies. Real life efficacy and safety of this combination were evaluated in HCV GT1b infected patients (mostly cirrhotics) with compensated liver disease who failed previous boceprevir or telaprevir based therapies more than a year before. Material and methods Data of previous protease inhibitor failure patients, treated with 3DAA+RBV for 12 weeks (GT1b and/or non-cirrhotics) or 24 weeks (non-GT1b cirrhotics), were retrospectively collected. Results Population characteristics: boceprevir/telaprevir-failure: 82/45, GT1b: 117, cirrhotic: 111 (87.4%). SVR12/24 was observed in 103/105 patients (98.1%) of those who reached either time point. Four SAEs reported: one death due to myocardial infarction, another due to recurrent hepatocellular carcinoma after achieving SVR12, two hospitalizations (elevation of transaminases, pneumonia). Grade ≥ 3 AEs or laboratory abnormalities were reported in < 10% of patients; they were transient in all patients. No early discontinuation of drugs due to SAE has been reported. Conclusions One year after previous failure of boceprevir or telaprevir based therapy, 12 weeks of 3DAA+RBV combination in HCV GT1b infected patients is similarly effective and safe as in those with no previous HCV therapy, even in the presence of cirrhosis. These findings might be of particular interest in settings where alternative therapies for such patients are not available or not affordable.

[Hepatitis C: diagnosis, anti-viral therapy, after-care. Hungarian consensus guideline].

Magyarorszagon 70000 egyen lehet fertőzott hepatitis C-virussal, nagyobbik reszuk nem tud a fertőzottsegeről. A fertőzes időben tortenő felfedezese es meggyogyitasa a beteg szempontjabol a munkakepesseg megőrzeset, az eletminőseg javulasat, a majzsugor es a majrak megelőzeset, valamint a betegsegmentes varhato elettartam meghosszabbodasat, mig a beteg kornyezete es a tarsadalom szempontjabol a tovabbfertőzes veszelyenek megallitasat, a kesőbbi sulyos majbetegsegekből adodo egeszsegugyi raforditasigeny jelentős csokkeneset eredmenyezi. A 2003 ota alkalmazott pegilalt interferon+ribavirin kettős kezelessel a hazankban dominaloan 1-es genotipussal fertőzott, korabban terapiaban nem reszesult betegek 40–45%-a, a korabban sikertelenul kezeltek 5–21%-a gyogyithato meg. 2011-ben a korabbiaknal lenyegesen hatekonyabb, ket uj, direkt antiviralis hatasu proteazgatlo szer kerult forgalomba (boceprevir es telaprevir). A keszitmenyek – az előrehaladott stadiumban levő majbeteg szamara – 2013 majusa ota hazankban is fi...Approximately 70,000 people are infected with hepatitis C virus in Hungary, and more than half of them are not aware of their infection. From the point of infected individuals early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases and complications (liver cirrhosis, liver failure and liver cancer) and can increase work productivity and life expectancy. Furthermore, these could from prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity, as a socioeconomic aspect. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can clear the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of a direct acting first generation protease inhibitor drug (boceprevir or telaprevir) to the dual therapy increases the chance of sustained viral response to 63-75% and 59-66%, respectively. These two protease inhibitors are available and financed for a segment of Hungarian patients since May 2013. Between 2013 and February 2015, other direct acting antivirals and interferon-free combination therapies have been registered for the treatment of chronic hepatitis C with a potential efficacy over 90% and typically with a short duration of 8-12 weeks. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. Non-invasive methods (elastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment accurate and timely molecular biology tests are mandatory. Eligibility for treatment is a subject of individual central medical review. Due to budget limitations therapy is covered only for a proportion of patients by the National Health Insurance Fund. Priority is given to those with urgent need based on a Hungarian Priority Index system reflecting primarily the stage of liver disease, and considering also additional factors, i.e., activity and progression of liver disease, predictive factors of treatment and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained viral response value in different patient categories with consensus between professional organizations, National Health Insurance Fund and patient organizations. More expensive therapies might be available upon co-financing by the patient or a third party. Interferon-free treatments and shorter therapy durations preferred as much as financially feasible. A separate budget is allocated to cover interferon-free treatments for the most-in-need interferon ineligible/intolerant patients, and for those who have no more interferon-based therapy option.

Real-World Virologic Response Rates and Prediction of Outcomes with Peginterferon Alfa-2a/Ribavirin in Hungarian HCV Genotype 1 Patients

Aim: Dual peginterferon/ribavirin therapy remains a viable option for patients with chronic hepatitis C, because of the high cost of Direct-acting Antiviral Agents (DAA). We assessed real-life practice and treatment outcomes in Hungarian treatment-naive HCV genotype 1-infected patients who received peginterferon alfa-2a/ ribavirin treatment. Methods: This analysis of patients enrolled in Hungary as part of a large, multinational cohort study (PROPHESYS) included treatment-naive patients with HCV genotype 1 mono-infection who were prescribed peginterferon alfa-2a plus ribavirin. Results: Of 654 patients included in the analysis, 68% completed ≥ 80% of the planned duration of treatment (93% and 87% received ≥ 80% of the planned doses of peginterferon alfa-2a and ribavirin, respectively) and 23% stopped treatment prematurely because of the insufficient virologic response. Virologic response rates (HCV RNA < 50 IU/mL) were 20.3%, 55.2%, and 63.3% by Week 4, 12, and at the end of treatment (EOT), respectively, and a sustained virologic response 24 weeks post-treatment (SVR24) was achieved in 45.9% of patients. In patients with a virologic response at EOT, the relapse rate was 27.4%. SVR24 rates were 63% in patients who received ≥ 80% of the planned treatment and 55% in patients with lower exposure. Treatment was prolonged to ≥ 72 weeks in 51 patients with HCV RNA ≥ 50 IU/mL at Week 12, and < 50 IU/mL at Week 24, among whom the SVR24 rate was 35%. Conclusion: This analysis shows that SVR24 rates achieved in randomized trials can be reproduced in real-world settings by maintaining high rates of adherence and compliance with responseguided therapy.

[Hungarian consensus guideline for the diagnosis and treatment of B, C, and D viral hepatitis].

More than 1% of the Hungarian population is infected with hepatitis B, C, or D viruses. Since 2006 the diagnostics and therapy of these infections are carried out in treatment centers according to national guidelines - since 2010 according to financial protocols. The consensus-based guidelines for 2012 are published in this paper. The guidelines stress the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection is pegylated interferon for 48 weeks or continuous entecavir therapy. The later must be continued for at least 6 months after hepatitis B surface antigen (HBsAg) seroconversion. Tenofovir disoproxil fumarat is not yet reimbursed by the National Health Insurance Fund. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Treatment naive chronic hepatitis C patients should initially receive pegylated interferon and ribavirin dual combination therapy. In genotype 1 infection if response is insufficient at 4 or 12 weeks one of the two new direct acting antivirals (boceprevir or telaprevir) should be added. The length of treatment is usually 48 weeks; in cases of extended early viral response shorter courses are recommended. Previous treatment failure patients with genotype 1 infection should receive a protease inhibitor backed triple combination therapy, mostly for 48 weeks. However, relapsers without cirrhosis and with extended rapid viral response, shorter telaprevir based combination therapy is sufficient. Drug-drug interactions as well as emergence of viral resistance are of particular importance. For genotype 2 or 3 HCV infections 24 weeks, for genotype 4 infections 24, 48 or 72 weeks of pegylated interferon plus ribavirin therapy is recommended in general. The guidelines published here become protocols when published as official publications of the Hungarian Health Authority.

Small bowel stromal tumors diagnosed by capsule endoscopy

UNLABELLED Small intestinal stromal tumors account for approximately 35% of all gastrointestinal stromal tumors. Gastrointestinal bleeding is considered as one of the main clinical symptoms for SISTs. Capsule endoscopy has brought revolution in small bowel diagnostics, as it is considered the best method of visualisation of the entire small intestine. Besides, it is well tolerated by patients and is accompanied by a low number of complications. It is also indicated as the first diagnostic method in gastrointestinal bleeding of obscure origin, following negative upper endoscopy and colonoscopy. CASE REPORT 2 patients (a male and a female, aged 58 and 69, respectively) presented with obscure gastrointestinal bleeding have been examined by capsule endoscopy after negative upper endoscopy and colonoscopy. Videorecords have been assessed in both cases by two independent experts. The capsule reached the Bauchin-valve in both cases during the 8 hours of the testing time and the entire small bowel was clearly visible. - Based on the capsule endoscopic images, for one of the two cases a tumor has been reported as the background of the small intestinal bleeding. In the other case we could mark the location of the bleeding, while we were unable to ascertain the type of the actively bleeding lesion during the test. In order to determine the accurate bleeding source double-balloon enteroscopy was performed in the second case. After surgery the histological and immunohistochemical tests have justified the presence of spindle cell GISTs. Taking into consideration the Fletcher-classification, for the tumor size and the mitotic index, both cases can be classified as a GIST of low malignant potential. CONCLUSIONS An early diagnosis and application of a definitive therapy become possible by using capsule endoscopy, therefore the chance of survival of the patients might be increased.