Trends of Late Presentation to Care in Patients with Chronic Hepatitis C during a 10-Year Period in Croatia.

Late presentation to care is the major obstacle to receiving treatment for chronic hepatitis C (CHC). Our aim was to analyze the prevalence and trends of late presenters (LP) at first consultations in Croatia during a 10-year period. This retrospective cross-sectional study included all adult CHC patients (n = 854) entering specialist medical care at the University Hospital for Infectious Diseases Zagreb between 2009 and 2018. LP was defined as liver stiffness measurement ≥ 9.5 kPa or biopsy METAVIR F ≥ 3. During the study period, mean patients' age increased from 37 to 52 years while HCV genotype distribution changed leading to the replacement of genotype 1b with 1a (g1b 32% to 21%; g1a 19% to 38%). A total of 320 (37.4%) were LP; they were older (47.5, IQR 40.5-57.6), and more commonly infected with g1b (34.1%) and g3 (42.5%). The prevalence of LP significantly increased from 31.9% in 2009 to 46.5% in 2018. Late presentation for care of CHC is increasing in Croatia suggesting a gap of diagnosing strategies in patients over 50 years.

Human Alveolar Echinococcosis, Croatia.

Alveolar echinococcosis is a parasitic disease caused by the tapeworm larval stage of Echinococcus multilocularis. This zoonotic disease has not been known to occur in Croatia. We report a confirmed case of human alveolar echinococcosis in a patient in Croatia who had never visited a known E. multilocularis-endemic area.

Distribution of hepatitis C virus genotypes and subtypes in Croatia: 2008-2015.

OBJECTIVE: Hepatitis C virus (HCV) genotyping is an important part of pre-treatment diagnostic algorithms as it guides the choice of therapeutic regimens. The aim of this study was to analyse the distribution of HCV genotypes in patients with chronic hepatitis C from Croatia in the period 2008-2015. METHODS: The study enrolled 3,655 anti-HCV positive patients with available results of HCV genotyping from the three largest national HCV genotyping laboratories. RESULTS: The majority of HCV-infected individuals enrolled in the study were male (70.7%). Analysis of age distribution in a subset of 2,164 individuals showed a mean age of 40.9 years (SD 11.77 years). Croatian patients were mostly infected with HCV genotype 1 (56.6%), followed by genotype 3 (37.3%), genotype 4 (4.2%) and genotype 2 (1.8%). Genotype 1 subtyping in a subset of 1,488 patients showed 54% (803/1,488) of 1b infections and 46% (685/1,488) of 1a infections. Percentages of genotype 1 were the highest in Central/Northwestern and Eastern Croatia and the lowest in the Central/Southern Adriatic Region. Genotype 3 was most frequently found in the Central/Southern Adriatic Region (49.1%) but represented only 17.5% of infections in Eastern Croatia (p < 0.001). CONCLUSIONS: The results of this nine-year retrospective analysis on the distribution of HCV genotypes and subtypes in 3,655 HCV-infected individuals from Croatia showed that the majority of infections can be attributed to genotypes 1 and 3 with absence of major changes in the molecular epidemiology of the two most frequent HCV genotypes infection in Croatia in the past 20 years.

Treatment of Elderly Patients with Chronic Hepatitis C: A Retrospective Cohort Study.

The prevalence of chronic hepatitis C increases in elderly patients. The aims of this study were to identify the factors associated with hepatocellular carcinoma (HCC) and end-stage liver disease development and to evaluate the efficacy and safety of pegylated interferon (PEG-IFNα) plus ribavirin (RBV) therapy in elderly patients. A retrospective cohort study included all consecutive pa-tients with hepatitis C virus (HCV) infection treated with PEG-IFNα+RBV between 2003 and 2013. Elderly patients had a higher frequency of poor prognostic factors including genotype 1 infec-tion, high fibrosis, and high fibrosis index based on four factors (FIB-4) score. The sustained virologic response (SVR) rate for genotype 1 was significantly lower (35.8% vs. 57.1%), while the frequency of PEG-IFNα (27.2% vs. 7.8%), RBV dose reduction (19.6% vs. 9.7%) and treatment discontinuation (13.0% vs. 4.1%) was significantly higher in elderly patients. However, age was not associated with SVR in multivariate analysis, and comparable SVR rates were achieved when adjusted for fibrosis score (Ishak ≤3: 66.7% vs. 69.8%). During the follow-up, HCC was diagnosed in 18 elderly patients (3 SVR+, 4 SVR- and 9 untreated patients). In conclusion, selected elderly patients can achieve comparable SVR rates as younger patients, but with a higher rate of side effects. Since complications of HCV infection occur more frequently in elderly patients, they should be given priority for antiviral therapy.

[Viralhepatitis. Croatian Consensus Statement 2013]. / Virusni hepatitis. Hrvatska konsenzus konferencija 2013.

Croatian Consensus Conferences on Viral Hepatitis took place in 2005 and 2009. Considering the numerous novel concepts on the epidemiology, diagnosis and management of viral hepatitis (chronic hepatitis C genotype 1 in particular) that have emerged in the past four years, a new Croatian Consensus Conference on Viral Hepatitis was held in Zagreb on February 28, 2013. The abridged text of the Croatian Consensus Conference on Viral Hepatitis 2013 presents the new concepts on the epidemiology of viral hepatitis, serologic and molecular diagnosis of viral hepatitis, determination of the IL-28 gene promoter polymorphism, fibrosis grading, algorithm for patient diagnostic follow up, treatment of chronic hepatitis C (genotypes 1-6) and hepatitis B, treatment of special populations (children, dialysis patients, transplanted patients, individuals with HIV/HCV co-infection), and therapy side effects.

[Treatment guidelines for patients with genotype 1 chronic hepatitis C infection]. / Preporuke za lijecenje bolesnika s kronicnim hepatitisom C genotipa 1.

Dual therapy based on the combination of pegylated interferon-alpha 2a or 2b (PEG IFN-alpha2) and ribavirin has been considered standard-of-care treatment for chronic hepatitis C genotype 1 up to 2011. The first generation of protease inhibitors, boceprevir and telaprevir, have been approved for clinical use in Europe and USA since 2011. Therefore, national guidelines for the treatment of chronic hepatitis C genotype 1 have been updated to include new and more efficient therapeutic options. Croatian guidelines are based on the results of registration clinical trials for boceprevir and telaprevir, national guidelines of several EU countries (United Kingdom, Sweden, Germany, France and Italy), EASL and AASLD recommendations, as well as on the results of chronic hepatitis C genotype 1 treatment with dual therapy at the national level. The Croatian guidelines include recommendations for treatment-naïve and treatment-experienced patients (based on the type of virologic response to the first-line treatment). In treatment-naïve patients with mild fibrosis and favorable predictors of treatment outcome, dual therapy is the recommended treatment option. In treatment-naïve patients with advanced fibrosis (F3 and F4) as well as in patients with moderate fibrosis (F2) and unfavorable predictors of treatment outcome (age > 40 years, non-CC IL-28B genotype, non-RVR), triple therapy is recommended. Triple therapy is also recommended for relapsers (irrespective of fibrosis stage) and partial responders with advanced fibrosis (F3 and F4). Lead-in treatment strategy during triple therapy is recommended for null-responders.

Chemokine CXCL10 at week 4 of treatment predicts sustained virological response in patients with chronic hepatitis C.

The aim of this study was to analyze the predictive value of CXCL9, CXCL10, and CXCL11 concentrations before and after 4 and 12 weeks of treatment with pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C infected with the hepatitis C virus genotype 1. The study included 46 adult patients (29 women and 17 men). Chemokine quantification in the serum was performed at baseline and after 1, 3, and 6 months of treatment by enzyme immunoassay. Chemokine responses were compared in patients achieving a sustained virological response to treatment (SVR, n=26) and the non-SVR group (n=20). The differences in the CXCL9 and CXCL10 concentrations between the SVR and non-SVR groups were statistically significant. A multivariant analysis showed a significant association between treatment failure and higher concentrations of CXCL10. A higher predictive value of CXCL10 concentrations after 4 weeks of treatment compared to pretreatment values has been found (area under the curve 0.9288 and 0.7942, respectively, P=0.016). CXCL10 concentrations above 250 pg/mL 4 weeks after the start of treatment were independently associated with non-SVR. In conclusion, the results of this study have shown that CXCL10 concentrations at the time of a rapid viral response (4 weeks) are better predictors of achieving SVR compared to baseline levels. Additionally, this study suggests an important role of CXCL9 as a biomarker of SVR in patients with chronic hepatitis C.

Treatment of chronic hepatitis C in Croatian war veterans: experiences from Croatian reference center for viral hepatitis.

AIM: To examine the risk factors, comorbidity, severity of liver disease, treatment course, and outcome in Croatian war veterans with chronic hepatitis C, especially those suffering from posttraumatic stress disorder (PTSD). METHODS: We collected medical records of 170 adult men diagnosed with chronic hepatitis C who started treatment with a combination of pegylated interferon-alpha and ribavirin between January 2003 and June 2009 at the Croatian Reference Centre for Viral Hepatitis. RESULTS: Participants' mean age was 43 ± 9 years. Among 170 participants, there were 37 war veterans (22%). The main risk factor in veteran patients were operative procedures with transfusions (46% vs 5% in non-veterans; P < 0.001) and in non-veteran patients intravenous drug use (42.1% vs 13%; P < 0.001). The average duration of infection was longer in war veterans (14.5 ± 3.4 vs 12.2 ± 7.2 years; P = 0.020). The percentage of PTSD comorbidity in the whole group was 11% (18/170) and in the war veterans group 49% (18/37). The prevalence of sustained virological response in patients with PTSD was 50% and in patients without PTSD 56%. Treatment reduction in patients with PTSD (33%) was higher than in patients without PTSD (12%; P = 0.030). CONCLUSION: Croatian war veterans are a group with high risk of chronic hepatitis C infection because many of them were wounded during the Croatian War 1991-1995. Considerations about PTSD as a contraindication for interferon treatment are unjustified. If treated, patients with PTSD have an equal chance of achieving sustained virological response as patients without PTSD.

Intravenous Drug Users Can Achieve a High Sustained Virological Response Rate: experience From Croatian Reference Center for Viral Hepatitis.

BACKGROUND: Hepatitis C virus (HCV) is one of the major infectious disease agents among injecting drug users (IVDUs). However, most of the IVDUs are not still treated. OBJECTIVES: To examine the treatment course, adherence, tolerability and safety profiles and SVR rates in IVDUs compared to non-IVDUs. PATIENTS AND METHODS: Demographic and clinical data were collected from medical records of 345 adult patients diagnosed with chronic hepatitis C (CHC) who were treated with a PEG-IFN-α and ribavirin in Croatian Reference Center for Viral Hepatitis in Zagreb between January 2003 and January 2010. Efficacy, safety and tolerability treatment profiles were analyzed in IVDUs vs. non-IVDUs. Positive predictors for treatment outcome were evaluated by univariate and multivariate logistic regression. RESULTS: A total of 106 (30.46%) IVDUs were identified. The IVDUs were mainly male (81.13% vs. 52.30%, P = 0.0001), young (mean ± SD age: 32.46 ± 5.33 y vs. 46.12 ± 11.48 y, P = 0.0001), had lower fibrosis and HAI score (measured by ISHAK) and shorter duration of infection (mean ± SD: 8.98 ± 5.87 vs. 16.79 ± 8.99 y, P = 0.0001) compared to non-IVDU group. In IVDUs, genotype 1a (24.52%) and 3a (38.68%) were predominant. There were no differences in completion rate between the two studied groups. IVDUs achieved a significantly higher rate of overall SVR (70.75% vs. 51.04%, P < 0.0009) and in genotypes 1 and 4 (65.08% vs. 48.73%, P = 0.0294) vs. non-IVDUs. Treatment discontinuation rates due to side-effects were not significantly different in IVDUs and non-IVDUs (2.83% vs. 7.11%, P = 0.1390). IVDU group had a higher rate of lost to follow-up (13.21% vs. 4.60%, P = 0.0071). There were no statistically significant differences in SVR rate between IVDUs with, or without substitution therapy (55.55% vs. 74.62%, P = 0.0866). Independent predictors of SVR were age < 40 years and genotypes 2 and 3. Type of PEG-IFN-α used was not associated with SVR. CONCLUSIONS: Treatment of CHC in IVDUs should strongly be encouraged as they have positive predictors for achieving SVR such as younger age, shorter duration of infection, and consequently favorable histological stage of the disease, and good adherence to treatment. There is no difference in safety and tolerability profiles of treatment in IVDUs compared to patients with no history of drug abuse.

Virological and immunological characteristics of fatal Epstein-Barr virus mononucleosis in a 17-year-old Caucasian male presenting with meningoencephalitis and hemophagocytic syndrome.

In this report, the authors present a detailed immunological and virological assessment of an immunocompetent 17-year-old Caucasian male with a fatal Epstein-Barr virus (EBV) infectious mononucleosis presenting with meningoencephalitis and hemophagocytic syndrome. The patient with serologically confirmed EBV infectious mononucleosis was admitted to the hospital because of 3 weeks' fever. Fine-needle aspiration of lymph nodes showed reactive hyperplasia with prominent hemophagocytosis. Percentages of intracellular interferon-gamma (IFN-gamma) in CD4(+) and CD8(+) T cells in the peripheral blood progressively increased during the course of disease (10.2% and 8.5% on day 35; 30.1% and 53.2% on day 44; 42.2% and 75.2% on day 50; 36.1% and 50.6% on day 59, respectively). On day 50, the patient developed meningoencephalitis. Brain computed tomography (CT) was normal. Brain magnetic resonance imaging (MRI) showed multifocal inflammatory lesions in frontal and temporal cortex of the right hemisphere as well as severe perivascular inflammatory reaction. The patient was treated with steroids, cyclosporin A, and methotrexate intratecally. Following treatment, EBV viremia in the blood and cerebrospinal fluid (CSF) decreased from pretreatment values (54,490 copies of EBV DNA/ml and 39,500 copies/ml, respectively) to 8715 copies/ml in the blood and 14,690 in the CSF. Despite treatment, the patient remained unconscious and died of sepsis and pneumonia 3 months after initial symptoms. Immunohistochemical staining showed the presence of EBV in both perivascular infiltrates and grey matter. Enhanced Th1 response as shown by high levels of IFN-gamma in peripheral blood lymphocytes may be a predictor of severe complications during acute EBV infection. Early implementation of immunosuppressive therapy in these patients should be considered.

Distribution of hepatitis C virus genotypes in Croatia--a 10 year retrospective study of four geographic regions.

The aim of this 10-year retrospective study was to investigate the distribution of HCV genotypes in patients with chronic hepatitis C monitored in the largest center for molecular diagnostics of HCV infection in Croatia. The study enrolled 1163 anti-HCV positive adults with detectable HCV RNA in the plasma. The patients were classified in four regions: Zagreb and surrounding continental area, Split, Slavonija and Rijeka. HCV genotyping was performed by using VERSANT HCV Genotyping Assay (LIPA) (Bayer Diagnostics, Puteaux Cedex, France). Statistical analysis was performed by using Statistica for Windows V.5.1. The majority of HCV infections in the study population were caused by genotypes 1 (58.8% of infected patients) and 3 (35.6%). Percentages of patients infected with subtypes 1b and 1a were 37.4% and 13.1%, respectively. Genotypes 2 and 4 were present in a very low percentage of patients (2.2% and 3.4%, respectively) while genotypes 5 and 6 were not detected. Analysis of regional differences in the distribution of HCV genotypes revealed similar percentages of subtype 3a and 1b infections in the Split region while the majority of infections in other regions were caused by subtype 1b. Infections with genotypes 2 and 4 were present in less than 5% of patients in all geographic regions. Analysis of an association between risk factors for infection and distribution of genotypes and subtypes in a subset of patients from the Split region confirmed the association between IVDU and subtype 3a. We conclude that the prevalence of HCV genotypes and subtypes follows the pattern of other Southern and Eastern European Countries with the predominance of subtypes 1b, 3a and 1a.

[Acute hepatitis C--an unresolved issue]. / Akutni hepatitis C--nerazjasnjena pitanja.

INTRODUCTION: The problem encountered on collecting a large number of cases of acute hepatitis C (AH-C) cases are the reduction in the incidence of new infections, clinically mild or completely asymptomatic disease, and absence of specific diagnostic tests to identify acute HCV infection and to distinguish it from acute exacerbation of chronic hepatitis C (CH-C). AIM, PATIENTS AND METHODS: The aim of this paper is to give an overview of 108 patients with AH-C hospitalized at Viral Hepatitis Unit, University Hospital of Infectious Diseases, during a 13-years period. Anti-HCV testing was started in 1990 and detection of HCV-RNA by PCR method in 1995. By epidemiologic data, we were able to distinguish patients with acute posttransfusion hepatitis C (PTH-C) from those with other risk factors. All patients were followed-up at the Outpatient Clinic for Viral Hepatitis in order to diagnose those who would develop persistent HCV infection and CH-C. Thirty-eight patients with acute PTH-C, were followed-up from 1991 till the end of 2003, 82% of them until 1994, because proper anti-HCV blood donors testing started in 1994 in Croatia. All of the patients with acute PTH-C had jaundice. RESULTS: The development of chronic hepatitis C occurred in 86% of untreated patients with acute PTH-C and 50% of patients treated with recombinant interferon-alfa (3 MU s.c. t.i.w.) monotherapy during six months. The chronic course of disease was recorded in 40% of patients with AH-C and other exposure risk factors. A patient with AH-C after needle-stick injury (HCV genotype 1b) was treated by recombinant interferon-alfa monotherapy (10 MU s.c. once daily) during 3 months without effect, then was switched to combination therapy with recombinant interferon-alfa (5 MU s.c. t.i.w.) + ribavirin 1200 mg daily for 12 months. Another patient with accidental blood exposure refused specific therapy. In the former patient, the treatment with high daily doses of interferon had no led to viral clearance, and virologic response was achieved after 6 months of combination therapy. In the untreated patient, spontaneous viral clearance occurred after 12 months. DISCUSSION AND CONCLUSION: There is convincing evidence from published studies that interferon monotherapy reduces the rate of AH-C progression to KH-C. Despite this evidence, there still are many issues that remain to be solved. What is unclear is whom to treat, when to start therapy, and what doses and duration of treatment to use? Maybe 12 months of standard combined therapy (recombinant interferon alfa 5 MU s.c. t.i.w. + ribavirin 800-1200 mg daily) in patients with AH-C genotype 1b is warranted. Evaluation of the efficacy of peginterferon monotherapy or in combination with ribavirin, and comparison of different doses and duration of treatment are needed.

[Hepatitis E in tourists to India]. / Hepatitis E kod putnika u Indiju.

Hepatitis E (HE) is a serious problem in developing countries worldwide, affecting in epidemics or as sporadic cases millions of people. Hepatitis E virus (HEV) is the main cause of enterically transmitted acute viral hepatitis, especially in tropic and subtropic areas. We presented two patients, our citizens who traveled to India, and contracted HE. The source of infection was contaminated drinking water in both of them. The diagnosis of HE was confirmed by the finding of anti-HEV antibodies of class IgG and IgM (ELISA) in acute phase, and by dissappearing of IgM anti-HEV in convalescent period. Thus, these patients are the first documented cases of imported sporadic HE in Croatia.