Antiviral treatment significantly reduces the levels of CXCL9, CXCL10 and CXCL11 in chronic hepatitis C.

In this study, we aimed to elucidate the changes in the immune response during antiviral treatment of patients with chronic hepatitis C, with an emphasis on the chemokine dynamics and their association with liver fibrosis. Serum concentrations of 12 chemokines. (CCL2, CCL3, CCL4, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10 and CXCL11) were measured in 32 patients with chronic hepatitis C before direct-acting antiviral treatment and after sustained virological response using bead-based flow cytometry. Chemokine levels were also measured in 14 sex- and age-matched healthy individuals. Concentrations of CXCL9, CXCL10, CXCL11 and CCL20 were significantly higher in chronic hepatitis C patients before direct-acting antiviral treatment compared to healthy individuals. We also observed a significant reduction in CXCL9, CXCL10 and CXCL11 levels after sustained virological response. Furthermore, we demonstrated a strong positive correlation between CXCL9, CXCL10 and CXCL11 levels before antiviral treatment. When considering liver fibrosis, we found significantly higher levels of CXCL10 and lower levels of CCL17 and CXCL5 in pre-treatment patients with severe fibrosis. None of the analysed chemokines were able to predict METAVIR fibrosis score reduction after sustained virological response. The results of this study emphasize the importance of proinflammatory pathways in liver fibrosis immunopathology during chronic hepatitis C. Finally, our results also characterized CXCL10 as the chemokine which most accurately distinguished pre-treatment CHC patients and healthy individuals.

A pilot sentinel surveillance system to monitor treatment and treatment outcomes of chronic hepatitis B and C infections in clinical centres in three European countries, 2019.

BackgroundThe World Health Organization European Action Plan 2020 targets for the elimination of viral hepatitis are that > 75% of eligible individuals with chronic hepatitis B (HBV) or hepatitis C (HCV) are treated, of whom > 90% achieve viral suppression.AimTo report the results from a pilot sentinel surveillance to monitor chronic HBV and HCV treatment uptake and outcomes in 2019.MethodsWe undertook retrospective enhanced data collection on patients with a confirmed chronic HBV or HCV infection presenting at one of seven clinics in three countries (Croatia, Romania and Spain) for the first time between 1 January 2019 and 30 June 2019. Clinical records were reviewed from date of first attendance to 31 December 2019 and data on sociodemographics, clinical history, laboratory results, treatment and treatment outcomes were collected. Treatment eligibility, uptake and case outcome were assessed.ResultsOf 229 individuals with chronic HBV infection, treatment status was reported for 203 (89%). Of the 80 individuals reported as eligible for treatment, 51% (41/80) were treated of whom 89% (33/37) had achieved viral suppression. Of 240 individuals with chronic HCV infection, treatment status was reported for 231 (96%). Of 231 eligible individuals, 77% (179/231) were treated, the majority of whom had received direct acting antivirals (99%, 174/176) and had achieved sustained virological response (98%, 165/169).ConclusionTreatment targets for global elimination were missed for HBV but not for HCV. A wider European implementation of sentinel surveillance with a representative sample of sites could help monitor progress towards achieving hepatitis control targets.

Distinct Expression Patterns of Genes Coding for Biological Response Modifiers Involved in Inflammatory Responses and Development of Fibrosis in Chronic Hepatitis C: Upregulation of SMAD-6 and MMP-8 and Downregulation of CAV-1, CTGF, CEBPB, PLG, TIMP-3, MMP-1, ITGA-1, ITGA-2 and LOX.

Background and Objectives: The aim of this study was to analyze the expression of genes on transcriptomic levels involved in inflammatory immune responses and the development of fibrosis in patients with chronic hepatitis C. Materials and Methods: Expression patterns of 84 selected genes were analyzed with real-time quantitative RT PCR arrays in the peripheral blood of treatment-naive patients with chronic hepatitis C and healthy controls. The panel included pro- and anti-fibrotic genes, genes coding for extracellular matrix (EMC) structural constituents and remodeling enzymes, cell adhesion molecules, inflammatory cytokines, chemokines and growth factors, signal transduction members of the transforming growth factor- beta (TGF-ß) superfamily, transcription factors, and genes involved in epithelial to mesenchymal transition. Results: The expression of SMAD-6 coding for a signal transduction TGF-beta superfamily member as well as MMP-8 coding for an ECM protein were significantly increased in CHC patients compared with controls. Conclusions: Chronic hepatitis C was also characterized by a significant downregulation of a set of genes including CAV-1, CTGF, TIMP-3, MMP-1, ITGA-1, LOX, ITGA-2, PLG and CEBPB encoding various biological response modifiers and transcription factors. Our results suggest that chronic hepatitis C is associated with distinct patterns of gene expression modulation in pathways associated with the regulation of immune responses and development of fibrosis.

Is elimination of HCV in 2030 realistic in Central Europe.

According to the recent data presented by Central-European HCV experts, the estimated prevalence of HCV is between 0.2% and 1.7% in certain countries in this region. There are no financial limitations to access to treatment in most countries. Patients in these countries have access to at least one pangenotypic regimen. The most common barriers to the elimination of HCV in Central Europe are a lack of established national screening programmes and limited political commitment to the elimination of HCV. Covid-19 has significantly affected the number of patients who have been diagnosed and treated, thus, delaying the potential elimination of HCV. These data suggest that the elimination of HCV elimination projected by WHO before 2030 will not be possible in the Central Europe.

Distribution of human papillomavirus genotypes in women with high-grade cervical intraepithelial lesions and cervical carcinoma and analysis of human papillomavirus-16 genomic variants.

AIM: To analyze the distribution of high-risk human papillomavirus (HR-HPV) genotypes and the diversity of HPV-16 genomic variants in Croatian women with high-grade squamous intraepithelial lesions (HSIL) and cervical carcinoma. METHODS: Tissue biopsy specimens were obtained from 324 women with histopathologically confirmed HSIL or cervical carcinoma, 5 women with low-grade SIL, and 49 women with negative histopathology. HR-HPV DNA was detected with Ampliquality HPV-type nucleic-acid hybridization assay, which identifies 29 different HPV genotypes. HPV-16 genomic variants were analyzed by an in-house sequencing. RESULTS: The most common HPV type in women with HSIL was HPV-16, detected in 127/219 (57.9%) specimens. HPV-16 was also the dominant type in squamous cell cervical carcinoma (46/69 or 66.7%) and in adenocarcinoma (18/36 or 50.0%). Out of 378 patients, 360 had HR-HPV (282 single infections and 79 multiple infections), 3 (0.8%) patients had low-risk HPV, and 15 (4%) tested negative. HPV-16 variants were determined in 130 HPV-16 positive specimens, including 74 HSIL and 46 carcinoma specimens. In HSIL specimens, 41 distinct variants were found, 98.6% belonging to the European branch and 1.4% belonging to the African branch. In cervical carcinoma specimens, 95% isolates grouped in 41 variants belonging to the European branch, one isolate (2.5%) belonged to the North American, and one (2.5%) to the Asian-American branch. CONCLUSION: HPV-16, mainly belonging to the European branch, was the most frequent HPV genotype in women from Croatia with histologically confirmed HSIL and cervical cancer.

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.

Nonalcoholic fatty liver disease as a risk factor for Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea while nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. The aim of this study was to determine whether NAFLD increases susceptibility to CDI. A retrospective cohort study included patients ≥ 65 years, treated with antimicrobial therapy ≥ 24 h, and hospitalized ≥ 72 h in a 36-month period. Three-hundred fourteen patients were included; 83 with NAFLD and 231 controls. Except for diabetes mellitus (37.35% vs. 25.11%, p = 0.0462) and obesity (18.07% vs. 8.23%, p = 0.0218) that were more frequent in NAFLD group, there were no differences in other comorbidities, hospital admissions, antibiotic therapy within 3 months, prescription, and duration of antibiotic therapy. Fourteen (16.9%) patients with NAFLD and 17 (7.4%) in control group developed in-hospital CDI (p = 0.0156). The Charlson Age-Comorbidity Index > 6 (OR 4.34, 95%CI 1.39-13.57), hospital admission within 3 months (OR 7.14, 95%CI 2.33-21.83), serum albumins < 28 g/L (OR 3.15, 95%CI 1.04-9.53), NAFLD (OR 3.27, 95%CI 1.04-10.35), eGFR < 40 (OR 4.89, 95%CI 1.61-14.88), treatment with piperacillin/tazobactam (OR 4.86, 95%CI 1.59-14.83), and carbapenems (OR 3.99, 95%CI 1.28-12.40) were independently associated with CDI. Our study identified NAFLD as an independent predictor of CDI.

Frequency of baseline NS5A resistance-associated substitutions in patients infected with genotype 1 of hepatitis C virus in Croatia.

The backbone of current treatment for chronic Hepatitis C virus (HCV) infection are direct-acting antivirals targeting viral nonstructural proteins (NS3, NS4A, NS5A, NS5B). To date, there are six NS5A inhibitors approved for treatment of chronic HCV infection. The presence of drug-associated resistance substitutions is mainly due to fast error-prone replication, showing differential frequency between genotypes and subtypes. The aim of this study was to determine the frequency of baseline resistance to NS5A protein inhibitors in patients with genotype 1 HCV in Croatia. Resistance-associated substitutions (RAS) were detected by Sanger sequencing of HCV NS5A region amplified from 84 patients followed by phylogenetic analysis and analysis with Geno2Pheno algorithm. The frequency of NS5A RAS was 14.3% and highly dependent on viral subtype. The overall frequency of NS5A RAS was higher in patients infected with HCV subtype 1b (24.2%) than in those infected with HCV subtype 1a (7.8%). Overall, three resistance-conferring mutations were detected (Q30R, M28T and Y93H) along with two mutations (M28V and L31I) that cause reduced susceptibility to NS5A inhibitors. Analysis of the sequences showed two distinct subtype 1a clades with RAS detected in 4.3% (1/23) clade I and 10.7% (3/28) clade II sequences. Only a few distinct NS5A RAS were detected suggesting a high degree of homogeneity of the viral population. High frequency of clinically relevant NS5A RAS in Croatia suggest that the analysis of frequency and patterns of resistance mutations in local populations and evaluation of their possible clinical impact could be beneficial.

Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe.

BACKGROUND: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. METHODS: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. RESULTS: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V (P < 0.001), and their co-presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32-3.10],P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties. CONCLUSIONS: Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence.

A very high prevalence of hepatitis C virus infection among patients undergoing hemodialysis in Kosovo: a nationwide study.

BACKGROUND: Patients on hemodialysis are at high risk for hepatitis C virus (HCV) infection if measures for effective control of HCV infection in the hemodialysis environment are not implemented. Whereas in developed countries isolated small-scale outbreaks of HCV in hemodialysis units are occasionally reported, HCV transmission in the hemodialysis environment still represents a substantial problem in low-resource countries. This study systematically assessed the prevalence of HCV infection among all patients at all hemodialysis centers in Kosovo, determined the HCV genotype distribution, and reviewed the main risk factors associated with HCV infection in this group of patients. METHODS: From January to March 2013, blood samples from all patients undergoing hemodialysis at all seven hemodialysis centers in Kosovo were collected. The samples were screened for the presence of anti-HCV antibodies, and seropositive samples were also tested for HCV RNA. Genotyping was performed by sequencing the core region of the HCV genome. Subsequently, face-to-face interviews were conducted with consented patients attending hemodialysis in December 2015 and with the management of all hemodialysis centers in Kosovo. RESULTS: The overall seroprevalence of HCV infection among hemodialysis patients in Kosovo was 53.0% (354/668), ranging from 22.3 to 91.1% at different centers. HCV RNA was detected in 323/354 (91.2%) seropositive patients. The most frequent HCV genotype was genotype 1a (62.2%), followed by genotypes 4d (33.1%), 1b (4.0%), and 2c (0.7%). The duration of hemodialysis and receiving dialysis at more than one center were identified as independent significant predictors of anti-HCV positivity. Shortage of staff, lack of resources, and inconsistent use of hygienic precautions and/or isolation strategies were observed. CONCLUSIONS: The prevalence of HCV infection among hemodialysis patients in Kosovo is extremely high. The relatively low prevalence of HCV infection in the general population, predominance of two otherwise rare HCV genotypes among hemodialysis patients, and longer history of hemodialysis as a predictor of HCV infection all indicate nosocomial transmission due to inappropriate infection control practices as the main transmission route.

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.

Pre-vaccination prevalence of high-risk human papillomaviruses (HPV) in women from Kosovo and their related sociodemographic characteristics.

OBJECTIVES: Kosovo's current health care system does not support organized nationwide cervical cancer screening and human papillomavirus (HPV) vaccination programs. To date, no reliable data are available on cervical cancer incidence and mortality in Kosovo, or on high-risk HPV (HR-HPV) prevalence and HPV type distribution. Our aim is to determinate the pre-vaccination prevalence and distribution of HR-HPVs and to assesses the associations between sociodemographic characteristics and increased risk of HPV infection in women from Kosovo. MATERIAL AND METHODS: Detection of HR-HPV DNA in cytologically evaluated cervical smears was performed using a clinically validated Abbott RealTime High Risk HPV test, Roche Linear Array HPV Genotyping Test, HPV52 type-specific real-time PCR and an in-house GP5+/GP6+/68 PCR. RESULTS: The crude overall prevalence of any of the HR-HPVs was estimated at 13.1% (26/199; 95% confidence interval (CI): 9.1-18.5%), with HPV16 being the most common type (7/26, 26.9%), followed by HPV31 and HPV51, each detected in 4/26 (15.4%) cervical specimens, HPV18, detected in 3/26 (11.5%) specimens, HPV52 and HPV66, each detected in 2/26 (7.7%) specimens, and HPV33, HPV45, HPV56, and HPV58, each detected in a single (3.9%) specimen. Women over 40 (OR = 0.36), older than 18 at sexual debut (odds ratio (OR) = 0.28), those that had delivered at least one child (OR = 0.32), and those that had a history of pregnancy termination (OR = 0.39) were at lower risk for HPV infection. CONCLUSION: Because more than 70% of cervical precancerous lesions could have been prevented in Kosovo using nationwide HPV-based cervical cancer screening and HPV vaccination, it is of outmost importance to implement both programs in the national health care system as soon as possible.

Combined Analysis of the Prevalence of Drug-Resistant Hepatitis B Virus in Antiviral Therapy-Experienced Patients in Europe (CAPRE).

BACKGROUND: European guidelines recommend treatment of chronic hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe. METHODS: A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum hepatitis B virus DNA in European tertiary referral centers. RESULTS: Data from 1568 patients were included. The majority (73.8%) were exposed to lamivudine monotherapy. Drug-resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n = 102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load, and lamivudine exposure (P < .001). CONCLUSIONS: These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.

The comparison of Th1, Th2, Th9, Th17 and Th22 cytokine profiles in acute and chronic HIV-1 infection.

The aim of this study was to compare cytokine expression on both gene and protein levels in acute and chronic phase of HIV type 1 (HIV-1) infection. Thirty four patients were enrolled for cytokine expression analysis on protein level in acute and chronic stage of HIV-1 infection. Using PCR array technology, expression of 84 cytokine genes was measured in 3 patients in acute and 3 patients in chronic stage of HIV-1 infection. Bead-based cytometry was used to quantify levels of Th1/Th2/Th9/Th17/Th22 cytokines. The results showed statistically significant increase of 13 cytokine gene expression (cd40lg, csf2, ifna5, il12b, il1b, il20, lta, osm, spp1, tgfa, tnfsf 11, 14 and 8) and downregulation of the il12a expression in chronic HIV type 1 infection. Concentrations of IL-10, IL-4 and TNF-α were increased in the acute HIV type 1 infection when compared to control group. During chronic HIV type 1 infection there was an increase of IL-10, TNF-α, IL-2, IL-6, IL-13 and IL-22 levels when compared to control group. Comparison of cytokine expression between two stages of infection showed a significant decrease in IL-9 concentration. This study showed changes in cytokine profiles on both gene and protein levels in different stages of HIV-infection.

[HEPATITIS E IN CROATIA ­ GUIDELINES FOR DIAGNOSIS AND TREATMENT].

Hepatitis E is attributed great attention as an emerging worldwide-distributed zoonosis. The clinical presentation varies from severe fulminant in underdeveloped to milder forms of diagnostically unrecognized hepatitis cases in developed countries. Chronic hepatitis E is more often described in subjects with transplanted solid organs and HIV disease. The diagnosis of hepatitis E is established by determination of anti-HEV IgM and IgG with Western blot confirmation and detection of HEV RNA. In Croatia, the first case of indigenous disease caused by HEV genotype 3 (HEV-3) was detected in 2012. In this paper we present current knowledge on hepatitis E supplemented by own results obtained at the University Hospital for Infectious Diseases in Zagreb and guidelines for diagnosis and treatment of immunocompetent and immunocompromised individuals. In the period from 2011-2014, HEV was tested in 1107 patients, of whom 117 (10.6%) had anti-HEV antibodies. Acute HEV infection was diagnosed in 25 (2.3%) patients. Considering the prevalence of antibodies we can conclude that HEV diagnostics should be included in the diagnostic panel for patients with elevated aminotransferases.

[Historical background of the Croatian Medical Association]. / Povijesni pregled razvoja Hrvatskoga Lijecnickog zbora.

Since the establishment of the Croatian Medical Association in 1874, continuing its socializing, collaborative, professional and scientific activities through generations of medical doctors and dental doctors down to the present time. The period has been marked by dedicated work of many generations of physicians, numerous professional and scientific achievements of the medical profession. During their mandates, many presidents guided and directed the activities of the CMA, fervently discussed and fought for progress and prosperity and proudly celebrated important anniversaries and events. Lijednicki vjesnik, the CMA journal, has always been an important factor in the education of its readers, as well as for professional and scientific advancement of many colleagues.

Steatotic Liver Disease and Sepsis Outcomes-A Prospective Cohort Study (SepsisFAT).

Background: While it has been shown that steatotic liver disease (SLD) is associated with systemic changes in immune response, the impact of SLD on sepsis outcomes has not yet been established. The aim of this study was to investigate the association between SLD and sepsis severity and outcomes. Methods: A prospective observational study included consecutively hospitalized adult patients with community-acquired sepsis during a 16-month period. Results: Of the 378 included patients (49.5% male, median age of 69, IQR 57-78 years), 174 (46%) were diagnosed with SLD. Patients with SLD were older and more frequently fulfilled the criteria for metabolic syndrome. There were no differences in the source and etiology of sepsis between the groups. Patients with SLD exhibited a higher incidence of acute kidney injury (29.3% vs. 17.6%), the need for renal replacement therapy (16.1% vs. 8.8%), and more frequent use of invasive mechanical ventilation (29.3% vs. 18.1%). In-hospital mortality was significantly higher in the SLD group (18.39% vs. 9.8%). The multivariable analysis indicated that SLD was associated with mortality (HR 2.82, 95% CI 1.40-5.71) irrespective of the other elements within metabolic syndrome. Conclusions: SLD might be associated with higher sepsis in-hospital mortality, and more frequent development of acute kidney and respiratory insufficiency requiring more critical care support.

The H1N1 influenza pneumonia as early complication after heart transplantation--experience from the Dubrava University Hospital, Zagreb, Croatia.

In April 2009, a novel influenza A (H1N1) virus was initially detected, and only after two months World Health Organization declared pandemic, while virus became globally present. We report here a confirmed case of patient suffering from H1N1 influenza pneumonia in an early period after heart transplantation. Complications of influenza A and B include viral pneumonia, secondary bacterial pneumonia and possibly acute allograft rejection in the setting of weaning of immunosuppression. In our case H1N1 influenza pneumonia was treated according to the published guidelines and had a mild course of disease, but nevertheless emphasis should be put on the prevention of disease applying known general infection control procedures and vaccination while disease course cannot be predicted.

[Screening for opportunistic infections and vaccination before introduction of biologic therapy]. / Probir na oportunisticke infekcije i cijepljenje prije pocetka bioloske terapije.

Patients on anti-TNFalpha medications carry a higher risk for developing opportunistic infections. In order to introduce anti-TNFalpha therapy, screening for hepatitis viruses B and C, HIV, EBV, HPV, TBC, bacterial, fungal and parasitic infections should be performed. Screening involves patient's history of earlier infectious diseases, vaccinations and traveling to parts of the world with endemic diseases. Clinical examination should be supplemented with stomatologic and gynecologic exams. Laboratory results include leukogram, transaminases, C-reactive protein, urine analysis, hepatitis B, C, HIV and EBV serology. Varicella zoster virus serology depends on past medical history. If the patient has traveled to tropical areas, both stool analysis and strongiloidiasis serology should be performed. Other mandatory examinations include chest radiography, PPD and TBC serology using interferon gamma release test (IGRA). If suspecting intra-abdominal abscess, magnetic resonance of the abdomen is recommended. In case of abscess, CMV or Clostridium difficile colitis anti-TNF-alpha therapy is contraindicated. Live vaccine application is contraindicated in patients receiving anti-TNFalpha therapy. All seronegative patients should be vaccinated against hepatitis B virus. Seasonal flu vaccination is recommended to be applicated yearly and pneumococcal polysaccharide vaccine once in every five years. Based on the past medical history and serologic results, patients are vaccinated against VZV with extra precaution. Human papilloma virus vaccination is performed in a group of women under 23 years of age, after gathering cervical smear sample analysis.

[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.