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U radu opisujemo mladu bolesnicu sa šećernom bolesti tipa I koja se zarazila virusom hepatitisa A (HAV) genotipa IB tijekom boravka u Burkini Faso. Prikaz bolesnice nedvojbeno potvrđuje važnost pridržavanja preporuka stručnih društava i nadležnih tijela o cijepljenju putnika., We describe a clinical case of hepatitis A in a young women with type I diabetes infected with genotype IB of hepatitis A virus (HAV) from Burkina Faso. The case confirms the importance of strict adherence to the recommendations by professional associations and institutions regarding vaccination of the travellers.

Epstein-Barr virus (EBV) is a widely disseminated herpesvirus for which antibodies have been demonstrated in over 90% of adults worldwide. After subclinical primary EBV infections, as well as after infectious mononucleosis, the virus can be shed in saliva for a prolonged period of time. Diseases and disorders that can induce EBV salivary shedding include mental disorders and sex, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, malaria and HIV infection. As the occurrence of EBV in saliva during acute infectious diseases has not been systematically researched so far, this pilot cross-sectional study aimed to investigate the possible relationship between acute infectious diseases and salivary shedding of EBV. A total of 40 patients with acute infectious diseases was enrolled, along with 41 adults free of acute infections. Peripheral venous blood samples for serodiagnosis and saliva samples for EBV PCR testing were collected from both groups. The most common acute infectious disease was COVID-19 pneumonia, followed by haemorrhagic fever with renal syndrome. Crude proportions of people with positive serological test results and those with saliva viral shedding were similar in the two groups. The presented preliminary data does not indicate acute infectious conditions as a marked “contributor” in increasing salivary EBV shedding.

Objectives: The purpose of this study was to determine if elevated concentration of soluble receptor tunica interna endothelial cell kinase-2 (Tie-2) in the amniotic fluid represent a risk factor for the subsequent development of preeclampsia (PE). Study design: Amniotic fluid samples were collected as a part of routine clinical diagnostics from women referred to clinical care due to genetic indications. A total of 12 women with preeclampsia and 26 normotensive pregnant women were included in the study. Mean gestational age at amniocentesis was 17.92 weeks of pregnancy in preeclampsia and 17.88 in control group, respectively. Concentrations of sTie-2 in the amniotic fluid were determined by a standardized enzyme immunoassay. Results: Median concentration of Tie-2 in the amniotic fluid of PE patients was lower (median 1.109 ng/ml) compared with normotensive pregnant women (median 1.433 ng/Ml) but the difference was not statistically significant (p = 0.2973). Concentration of sTie-2 in the amniotic fluid did not significantly correlate with maternal age, gestational age at amniocentesis or delivery, as well as weight or length at birth. A difference in the gestational age at delivery in PE patients (mean 37.7 weeks) and normotensive pregnant controls (mean 39.8 weeks) was statistically significant (p = 0.0003). Birth weight and length of children delivered by PE women (mean 2863.3 g and 48.3 cm) were significantly lower compared with normal pregnancies (mean 3591.2 g and 51.4 cm, p = 0.0002 and p = 0.006, respectively). Conclusion: Our results suggest that amniotic fluid concentrations of sTie-2 do not predict development of PE and that further studies on biomarkers as predictors of PE should include other angiogenic biological response modifiers.

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged

RNA viruses are characterised by extremely high genetic variability due to fast replication, large population size, low fidelity, and (usually) a lack of proofreading mechanisms of RNA polymerases leading to high mutation rates. Furthermore, viral recombination and reassortment may act as a significant evolutionary force among viruses contributing to greater genetic diversity than obtainable by mutation alone. The above-mentioned properties allow for the rapid evolution of RNA viruses, which may result in difficulties in viral eradication, changes in virulence and pathogenicity, and lead to events such as cross-species transmissions, which are matters of great interest in the light of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemics. In this review, we aim to explore the molecular mechanisms of the variability of viral RNA genomes, emphasising the evolutionary trajectory of SARS-CoV-2 and its variants. Furthermore, the causes and consequences of coronavirus variation are explored, along with theories on the origin of human coronaviruses and features of emergent RNA viruses in general. Finally, we summarise the current knowledge on the circulating variants of concern and highlight the many unknowns regarding SARS-CoV-2 pathogenesis.

West Nile Virus Neuroinvasive Disease (WNV NID) requires prolonged intensive care treatment, resulting in high mortality and early disability. Long-term results are lacking. We have conducted an observational retrospective study with a prospective follow-up of WNV NID patients treated at the Intensive Care Unit (ICU), University Hospital for Infectious Diseases, Zagreb, Croatia, 2013–2018. Short-term outcomes were vital status, length of stay (LOS), modified Rankin Scale (mRS), and disposition at discharge. Long-term outcomes were vital status and mRS at follow-up. Twenty-three patients were identified, 78.3% males, median age 72 (range 33–84) years. Two patients (8.7%) died in the ICU, with no lethal outcomes after ICU discharge. The median ICU LOS was 19 days (range 5–73), and the median hospital LOS was 34 days (range 7–97). At discharge, 15 (65.2%) patients had moderate to severe/mRS 3–5, 6 (26.0%) had slight disability/mRS 2–1, no patients were symptom-free/mRS 0. Ten (47.6%) survivors were discharged to rehabilitation facilities. The median time to follow-up was nine months (range 6–69). At follow-up, seven patients died (30.5%), five (21.7%) had moderate to severe/mRS 3–5, one (4.3%) had slight disability/mRS 2–1, six (26.1%) had no symptoms/mRS 0, and four (17.4%) were lost to follow-up. Briefly, ten (43.5%) survivors improved their functional status, one (4.3%) was unaltered, and one (4.3%) aggravated. In patients with severe WNV NID, intensive treatment in the acute phase followed by inpatient rehabilitation resulted in significant recovery of functional status after several months.

Hepatitis C vodeći je uzrok kronične bolesti jetre, hepatocelularnog karcinoma i važna indikacija za transplantaciju jetre. Glavni cilj liječenja je postizanje trajnog virološkog odgovora koji označava negativnu viremiju 12 tjedana nakon završetka liječenja (SVR, od engl. sustained virological response). Uvođenjem antivirusnih lijekova s izravnim djelovanjem, povećala se stopa SVR-a, skratilo vrijeme trajanja terapije i utjecalo se na stadij fibroze i steatoze jetre nakon liječenja. Cilj ovog rada bio je analizirati promjenu stadija fibroze (F1-F4) i steatoze (S0-S3) primjenom tranzijentne elastografije u prethodno neliječenih bolesnika s kroničnim hepatitisom C (n=205) koji su postigli trajni virološki odgovor, a bili liječeni isključivo direktno djelujućim antivirusnim lijekovima (DAA).

The hepatitis A virus (HAV) is a highly hepatotropic virus transmitted mainly via the fecal–oral route. The purpose of this study is to describe a prolonged HAV outbreak in HIV-infected men who have sex with men (MSM) and pre-exposure prophylaxis (PrEP) users in Croatia in 2022. Croatia has a centralized system of HIV care and the PrEP service is only available at the University Hospital for Infectious Diseases (UHID), Zagreb. We reviewed all MSM living with HIV and MSM PrEP users at UHID and identified those diagnosed with HAV between January and October 2022. During this period, a total of 1036 MSM living with HIV and 361 PrEP users were followed, and 45 (4.4%) and 32 (8.9%) were diagnosed with HAV, respectively. Most cases were diagnosed in mid-February. A total of 70.1% (726/1036) MSM living with HIV and 82.3% (297/361) PrEP users were susceptible to HAV. Sequencing information was available for 34 persons; in all cases the HAV subtype IA was found. Our findings indicate that both MSM living with HIV and HIV-uninfected PrEP users are vulnerable to HAV infection and might be a potential source for a more widespread HAV epidemic.

Identifying individuals recently infected with HIV has been of great significance for close monitoring of HIV epidemic dynamics. Low HIV sequence ambiguity (SA) has been described as a promising marker of recent infection in previous studies. This study explores the utility of SA defined as a proportion of ambiguous nucleotides detected in baseline pol sequences as a tool for routine real-time surveillance of HIV incidence trends at a national level. A total of 353 partial HIV-1 pol sequences obtained from persons diagnosed with HIV infection in Slovenia from 2000 to 2012 were studied, and SA was reported as a percentage of ambiguous base calls. Patients were characterized as recently infected by examining anti-HIV serological patterns and/or using commercial HIV-1 incidence assays (BED and/or LAg-Avidity assay). A mean SA of 0.29%, 0.14%, and 0.19% was observed for infections classified as recent by BED, LAg, or anti-HIV serological results, respectively. Welch's t-test showed a significant difference in the SA of recent versus long-standing infections (p < 0.001). CD4+ T-cell counts ≤250 cells/mm3 significantly correlated with higher SA (p < 0.001), whereas the homo/bisexual transmission route significantly correlated with lower SA (p = 0.005). When the LAg-assay was used as an indicator of recent infection, a receiver operating characteristic curve with the largest area under the curve (0.896) was observed for SA (sensitivity and specificity of 79%), indicating the best correlation of the data. A reliable estimation of the trends of HIV incident infection could be inferred from measuring SA irrespective of the cutoff used ; however, in Slovenia it seems that lower cutoffs are more appropriate. Our data suggest that SA could be used as a real-time surveillance tool for close monitoring of HIV incidence trends, especially in countries where baseline HIV resistance genotyping is performed routinely, rendering this approach cost-effective.

Epstein-Barr virus (EBV) or human herpesvirus 4 (HHV-4) is a ubiquitous human oncogenic virus, and the first human virus found to express microRNAs (miRNAs). Its genome contains two regions encoding more than 40 miRNAs that regulate expression of both viral and human genes. There are numerous evidences that EBV miRNAs impact immune response, affect antigen presentation and recognition, change T- and B-cell communication, drive antibody production during infection, and have a role in cell apoptosis. Moreover, the ability of EBV to induce B-cell transformation and take part in mechanisms of oncogenesis in humans is well known. Although EBV infection is associated with development of various diseases, the role of its miRNAs is still not understood. There is abundant data describing EBV miRNAs in nasopharyngeal carcinoma and several studies that have tried to evaluate their role in gastric carcinoma and lymphoma. This review aims to summarize so far known data about the role of EBV miRNAs in altered regulation of gene expression in human cells in EBV-associated diseases.

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.

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.

We report an HIV-infected person who was treated for lymphogranuloma venereum cervical lymphadenopathy and proctitis in Croatia in 2014. Infection with a variant L2b genovar of Chlamydia trachomatis was detected in a cervical lymph node aspirate. A prolonged course of doxycycline was required to cure the infection.

Hepatitis C vodeći je uzrok kronične bolesti jetre, hepatocelularnog karcinoma i važna indikacija za transplantaciju jetre. Glavni cilj liječenja je postizanje trajnog virološkog odgovora koji označava negativnu viremiju 12 tjedana nakon završetka liječenja (SVR, od engl. sustained virological response). Uvođenjem antivirusnih lijekova s izravnim djelovanjem, povećala se stopa SVR-a, skratilo vrijeme trajanja terapije i utjecalo se na stadij fibroze i steatoze jetre nakon liječenja. Cilj ovog rada bio je analizirati promjenu stadija fibroze (F1-F4) i steatoze (S0-S3) primjenom tranzijentne elastografije u prethodno neliječenih bolesnika s kroničnim hepatitisom C (n=205) koji su postigli trajni virološki odgovor, a bili liječeni isključivo direktno djelujućim antivirusnim lijekovima (DAA)., Hepatitis C is the leading cause of chronic liver disease, hepatocellular carcinoma and an important indication for liver transplantation. The main objective of the treatment is to achieve a sustained virological response defined as a negative HCV RNA 12 weeks after completion of therapy (SVR). Direct-acting antivirals have been developed to treat chronic HCV infection. They have resulted in increased SVR rates, shorter and simpler treatment regimens, and minimal adverse effects. The aim of this study was to analyze the change in the stage of fibrosis (F1-F4) and steatosis (S0-S3) using transient elastography in treating naive patients with chronic hepatitis C (n = 205) who achieved a sustained virological response and were treated exclusively with directly acting antiviral drugs (DAA).

Molecular epidemiology of HIV-1 infection in treatment-naive HIV-1 infected persons from Croatia was investigated. We included 403 persons, representing 92.4% of all HIV-positive individuals entering clinical care in Croatia in 2014–2017. Overall prevalence of transmitted drug resistance (TDR) was estimated at 16.4%. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside RTI (NNRTIs) and protease inhibitors (PIs) was found in 11.4%, 6.7% and 2.5% of persons, respectively. Triple-class resistance was determined in 2.2% of individuals. In addition, a single case (1.0%) of resistance to integrase strand-transfer inhibitors (InSTIs) was found. Deep sequencing was performed on 48 randomly selected samples and detected additional TDR mutations in 6 cases. Phylogenetic inference showed that 347/403 sequences (86.1%) were part of transmission clusters and identified forward transmission of resistance in Croatia, even that of triple-class resistance. The largest TDR cluster of 53 persons with T215S was estimated to originate in the year 1992. Our data show a continuing need for pre-treatment HIV resistance testing in Croatia. Even though a low prevalence of resistance to InSTI was observed, surveillance of TDR to InSTI should be continued.

Resistance of Human Immunodeficiency Virus (HIV) to antiretroviral drugs is an important limitation in achieving complete suppression of viral replication and therefore represents an important clinical issue. It refers especially to therapy-naive individuals infected with resistant HIV strains, e.g. individuals with transmitted drug resistance (TDR). Transmitted drug resistance mutations (TDRMs) are clinically relevant and may reduce the efficacy of antiretroviral therapy. In this paper, we report the first case of HIV-1 transmitted triple-class drug resistance in Croatia. The aim of this study was to characterize drug resistance patterns and TDRMs in the newly diagnosed, treatment-naive HIV-1 patient with such a complex resistance pattern. Sanger sequencing (SS) of the sample showed four reverse transcriptase inhibitor (RTI) resistance mutations (E44D, T215E, K103N, L100I) affecting two drug classes and two protease inhibitor resistance mutations (V32I, I47V). To characterize HIV-1 minority drug resistance variants below the detection limit of SS, deep sequencing (DS) analysis was performed. DS analysis identified the same triple class resis- tance pattern that was identified by SS with addition of several other RTI mutations. The patient described in this report is the first patient with HIV-1 triple-class resistance in Croatia and further studies will be directed toward analysing possible local onward transmission of this resistant virus., Rezistencija virusa humane imunodeficijencije (HIV) na antiretrovirusne lijekove sprječava supresiju virusne replikacije te predstavlja značajan izazov u kliničkoj medicini. Posebno valja istaknuti problem primarne rezistencije (engl. transmitted drug resistance, TDR) koja se odnosi na prethodno neliječene osobe koje su zaražene rezistentnim sojevima HIV-a. Mutacije koje su pov- ezane s primarnom rezistencijom (engl. transmitted drug resistant mutations, TDRM) su klinički značajne i mogu nepovoljno djelovati na učinkovitost antiretrovirusnog liječenja. U ovom je radu opisana prva osoba s primarnom rezistencijom HIV-a na 3 klase antiretrovirusnih lijekova u Hr- vatskoj. Cilj ovog istraživanja bio je analizirati obrasce primarne rezistencije i TDRM u novodi- jagnosticiranog i neliječenog HIV-om zaraženog pojedinca. Primjenom Sangerovog sekvenciranja (SS) dokazali smo četiri mutacije povezane s rezistencijom na inhibitore reverzne transkriptaze (E44D, T215E, K103N, L100I) koje smanjuju osjetljivost na dvije klase lijekova (nukleozidne analoge inhibitore reverzne transkriptaze i nenukleozidne inhibitore reverzne transkriptaze) kao i dvije mutacije (V32I, I47V) povezane s rezistencijom na inhibitore proteaze. U svrhu identifikacije mogućeg postojanja manjinskih rezistentnih varijante ispod granice detekcije SS-a, provedena je analiza dubinskim sekvenciranjem (DS). DS analiza identificirala je isti obrazac rezistencije na 3 klase antiretrovirusnih lijekova identificiran s SS uz nekoliko dodatnih mutacija. U ovom je radu opisan prvi slučaj primarne rezistencije HIV-a na 3 klase antiretrovirusnih lijekova, a buduća istraživanja analizirat će moguće putove transmisije ovog rezistentnog virusa u Hrvatskoj.

Ciljevi: Rezistencija HCV-a na direktno djelujuće antivirusne lijekove (DAA) predstavlja potencijalno ograničenje efikasnosti antivirusnog liječenja, naročito mutacija Y93H koja se povezuje s klinički značajnom rezistencijom na prvu generaciju NS5A inhibitora. Cilj ovog istraživanja bio je razjasniti prvi slučaj bolesnice u Hrvatskoj inficirane HCV-om genotipa 3a i mutacijom Y93H koja nije postigla SVR12 nakon 8 tjedana liječenja s glecaprevirom/pibrentasvirom. Metode: Rutinskom dijagnostičkom obradom bolesnice provedenom prilikom ulaska u kliničku skrb određeni su viremija i genotip virusa. Sekvenciranjem regije NS5A virusa Sangerovom metodom te analizom sekvenci u algoritmu Geno2Pheno detektirana je prisutnost Y93H mutacije. Rezultati: Pedesetdevetogodišnja bolesnica inficirana je 1991. putem transfuzije krvi. Unatoč dugom trajanju infekcije, tranzijentnom elastografijom detektiran je nizak stadij fibroze jetre (F1, 7.4 kPa) bez značajnih komorbiditeta. Bolesnica nije prethodno bila liječena DAA te imala početnu viremiju 7, 659, 530 IU/ml HCV RNA. Liječenje je provedeno tijekom 8 tjedana pri čemu je uslijedio brzi pad viremije uz nedetektabilnu HCV RNA (

A 70-year-old patient was admitted to the Department of Oral Medicine for multiple oral ulcerations on the left buccal mucosa, around 0.5 cm in diameter, as well as on the gingiva. Otherwise, the patient suffered from chronic lymphocytic leukemia, hypogammaglobulinemia, chronic renal insufficiency, with complete afunction of the right kidney, asthma, hypertension, gastritis and prostate hyperplasia. Differential diagnosis of oral ulcerations included drug induced oral ulcerations, paraneoplastic pemphigus, viral ulcerations (cytomegalovirus, herpes simplex viruses), fungal ulcerations (candidiasis, aspergillosis, histoplasmosis, cryptococcosis) and bacterial ulcerations, as well as neutropenic ulcers. One of the possible explanations was that the lesions were due to the use of drugs, the more so as oral lesions evolved when the doses of allopurinol and chlorambucil were increased, and subsided when the doses of both drugs were decreased. However, we could not establish for sure whether the lesions were due to allopurinol or chlorambucil. According to literature data, allopurinol is one of the most frequent drugs known to induce skin adverse reactions, therefore we assumed that it was the culprit drug. Unfortunately, several weeks later the patient died from sepsis, pneumonia with respiratory insufficiency and multiorgan failure.

Background and aims: Genetic polymorphisms of immune mediators have been associated with differences in the natural course of chronic hepatitis C (CHC). The aim of this study was to analyze the association of IL-1β gene polymorphism with the stage of liver fibrosis (LF), grade of necroinflammatory activity (NIA) and fibrosis progression rate (FPR) in CHC patients. Patients and methods: The study included 50 treatment-naive Croatian CHC patients (36 male and 14 female ; age median 37.5 years) with elevated ALT. Diallele polymorphism (C/T) at locus -31 in the IL-1β gene promoter region was determined by restriction fragment length polymorphism (RFLP). Stage of LF and NIA were assessed from liver biopsy sample according to Ishak classification. Results: There was no difference in the stage of LF and NIA level between particular patient genotypes. However, patients with at least 1 C allele at locus -31showed significantly faster FPR than those with no C allele (0.4 vs. 0.258 Ishak's units/year ; p = 0.043). Higher stages of fibrosis were observed in older patients (p = 0.001) and those infected at an older age (p = 0.017). Conclusion: Our study demonstrated that the carriage of at least 1 C allele at -31 locus of IL-1β gene led to faster progression of LF in CHC patients with a biochemically active disease, but did not determine the final stage of fibrosis development. Combined with other risk factors, this finding may serve as a genetic marker to identify patients that require earlier introduction of therapy, since delay could hamper therapeutic success due to rapid disease progression

Background and aims: Genetic polymorphisms of immune mediators have been associated with differences in the natural course of chronic hepatitis C (CHC). The aim of this study was to analyze the association of IL-1β gene polymorphism with the stage of liver fibrosis (LF), grade of necroinflammatory activity (NIA) and fibrosis progression rate (FPR) in CHC patients. Patients and methods: The study included 50 treatment-naive Croatian CHC patients (36 male and 14 female; age median 37.5 years) with elevated ALT. Diallele polymorphism (C/T) at locus -31 in the IL-1β gene promoter region was determined by restriction fragment length polymorphism (RFLP). Stage of LF and NIA were assessed from liver biopsy sample according to Ishak classification. Results: There was no difference in the stage of LF and NIA level between particular patient genotypes. However, patients with at least 1 C allele at locus -31showed significantly faster FPR than those with no C allele (0.4 vs. 0.258 Ishak's units/year; p = 0.043). Higher stages of fibrosis were observed in older patients (p = 0.001) and those infected at an older age (p = 0.017). Conclusion: Our study demonstrated that the carriage of at least 1 C allele at -31 locus of IL-1β gene led to faster progression of LF in CHC patients with a biochemically active disease, but did not determine the final stage of fibrosis development. Combined with other risk factors, this finding may serve as a genetic marker to identify patients that require earlier introduction of therapy, since delay could hamper therapeutic success due to rapid disease progression.

U razdoblju od 2008. do 2017. u Klinici za infektivne bolesti "Dr. Fran Mihaljević" u Zagrebu liječeno je 210 bolesnika s kroničnom HBV infekcijom koji su imali histološku i biokemijsku aktivnost bolesti. Stadij fibroze određivan je patohistološki i elastografski. Cirozu je već u početku imalo 14,5 % bolesnika. Iako je funkcionalno izlječenje bilo rijetko (5,5 % slučajeva) kod većine bolesnika postignuta je supresija virusne replikacije, usporavanje ili prekid razvoja fibroze, pa čak i regresija stadija fibroze za jedan stupanj po Metaviru u 16 % bolesnika. Zapaženo je smanjenje frekvencije pojave dekompenzirane ciroze i hepatocelularnog karcinoma za 2 do 3 puta u usporedbi s podacima kod neliječenih bolesnika. Bolesnici liječeni lamivudinom imali su visoku incidenciju razvoja rezistencije (32 % nakon 5 godina liječenja), te je terapija nastavljena tenofovirom uz većinom dobru podnošljivost i bez razvoja rezistencije. HBeAg nije se pokazao kao značajan prediktor težine i toka bolesti. Značajan je broj hematoloških i drugih imunosuprimiranih bolesnika (n = 24), koji terapiju primaju radi prevencije reaktivacije latentne HBV infekcije., A total of 210 patients with chronic HBV infection and histological and biochemical activity of disease were treated at the University Hospital for Infectious Diseases "Dr. Fran Mihaljević" in Zagreb in the period from 2008 to 2017. The fibrosis stage was determined histologically and by transient elastography, and cirrhosis was found initially in 14,5 % of the patients. Although functional recovery was rare (5.5 % of cases), the suppression of viral replication, slowing down or discontinuation of fibrosis progression was achieved in most of the treated. Even fibrosis regression by one stage in Metavir scale was achieved in 16 % of patients. There was also a decrease in the frequency of development of decompensated cirrhosis (2 patients) and hepatocellular carcinoma (2 patients) by 2 to 3 times in comparison to historical controls in nontreated patients. Patients treated with lamivudine had a high incidence of resistance development (32 % after 5 years). They continued therapy with tenofovir with good tolerability and no resistance development. HBeAg did not seem to be a significant predictor for the severity and the course of the disease. There is also a significant number of hematologic and other immunosuppressed patients (n = 24) receiving treatment to prevent the reactivation of latent HBV infection.

Slovenia is a small European country with a total of 547 HIV-infected individuals cumulatively reported by the end of 2011. However, the estimated incidence rate of HIV infections increased from 7.0 per million in 2003 to 26.8 per million in 2011. In this study, we assessed the prevalence of transmitted drug resistance (TDR) in the past 6 years (2005-2010) and analyzed the time trend of the proportion of men having sex with men (MSM) and HIV-1 subtype B among newly diagnosed individuals in a 15-year period (1996-2010) in Slovenia. Among 150 patients included in the study, representing 63% of HIV-1 newly diagnosed patients in 2005-2010, TDR was found in seven patients (4.7%). The prevalence of TDR to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors was 2% (3/150), 2% (3/150), and 0.7% (1/150), respectively. The majority of patients were infected with subtype B (134/150, 89%), while subtype A was detected in 6.0% (9/150), subtype D in 1.3% (2/150), and subtype G and CRF02_AG in 0.7% (one patient each). Three of 150 sequences could not be typed. Infection with subtype B was found to be significantly associated with male gender, Slovenia being reported as the country of the patient's nationality and origin of the virus, CDC class A, mode of transmission with homosexual/bisexual contact, sex with an anonymous person, and a higher CD4(+) count. Among patients carrying the subtype B virus, an MSM transmission route was reported in 87% of patients. Although the prevalence of TDR in Slovenia is still below the European average, active surveillance should be continued, especially among MSM, the most vulnerable population for HIV-1 infection in this part of Europe.

A 70-year-old patient was admitted to the Department of Oral Medicine for multiple oral ulcerations on the left buccal mucosa, around 0.5 cm in diameter, as well as on the gingiva. Otherwise, the patient suffered from chronic lymphocytic leukemia, hypogammaglobulinemia, chronic renal insufficiency, with complete afunction of the right kidney, asthma, hypertension, gastritis and prostate hyperplasia. Differential diagnosis of oral ulcerations included drug induced oral ulcerations, paraneoplastic pemphigus, viral ulcerations (cytomegalovirus, herpes simplex viruses), fungal ulcerations (candidiasis, aspergillosis, histoplasmosis, cryptococcosis) and bacterial ulcerations, as well as neutropenic ulcers. One of the possible explanations was that the lesions were due to the use of drugs, the more so as oral lesions evolved when the doses of allopurinol and chlorambucil were increased, and subsided when the doses of both drugs were decreased. However, we could not establish for sure whether the lesions were due to allopurinol or chlorambucil. According to literature data, allopurinol is one of the most frequent drugs known to induce skin adverse reactions, therefore we assumed that it was the culprit drug. Unfortunately, several weeks later the patient died from sepsis, pneumonia with respiratory insufficiency and multiorgan failure., Bolesnik u dobi od 70 godina upućen je na Zavod za oralnu medicinu zbog nekoliko oralnih ulceracija na lijevoj obraznoj sluznici veličine oko pola centimetra u promjeru te na gingivi. Inače je bolovao od kronične limfocitne leukemije, hipogamaglobulinemije, kronične bubrežne insufi cijencije s potpunom afunkcijom desnog bubrega, astme, hipertenzije, gastritisa i hiperplazije prostate. Diferencijalna dijagnoza oralnih ulceracija uključivala je oralne ulceracije uslijed uzimanja lijekova, paraneoplastični pemfi gus, virusne ulceracije (citomegalovirus, herpes simpleks viruse), gljivične ulceracije (kandidijaza, aspergiloza, histoplazmoza, kriptokokoza), bakterijske ulceracije te neutropenične ulceracije. Jedno od mogućih objašnjenja je bilo da su lezije vjerojatno nastale uslijed uzimanja lijekova, jer su se pojavile kada se doza alopurinola i klorambucila povećala, a počele su nestajati kada se doza tih lijekova smanjila. Ipak, nismo sigurni koji je od ova dva lijeka doveo do nastanka lezija, jer je nažalost nekoliko tjedana poslije bolesnik izdahnuo uslijed sepse, pneumonije i respiracijske insuficijencije te višeorganskog zatajenja.

Polimorfizam jednog nukleotida (engl. single nucleotide polymorphism, SNP) rs12979860 u blizini promotora gena za interleukin-28B (IL-28B) tj. genotipizacija IL-28B povezana je s prirodnim tijekom infekcije virusom hepatitisa C kao i s odgovorom na antivirusno i imunomodulacijsko liječenje kombinacijom pegiliranog interferona alfa i ribavirina (tzv. dvojna terapija). U eri direktno djelujućih antivirusnih lijekova genotip IL-28B više nije značajan prediktor ishoda liječenja no i dalje je važan parametar koji određuje prirodni tijek povijesti HCV infekcije. U zemljama koje nemaju univerzalni pristup novim terapijskim opcijama genotipizacija IL-28B i dalje se primjenjuje u pred-terapijskoj obradi bolesnika koji se liječe dvojnom terapijom. Cilj ovog rada bio je analizirati rezultate genotipizacije IL-28B (udio homozigota za T i C alel te heterozigota) u 595 bolesnika s kroničnim hepatitisom C koji su bili uključeni u kliničku skrb Zavoda za virusni hepatitis Klinike za infektivne bolesti "Dr. Fran Mihaljević" u Zagrebu od siječnja 2013. do prosinca 2015. g. SNP rs12979860 detektiran je metodom lančane reakcije polimerazom u stvarnom vremenu. Analiza SNP-a rs12979860 u genu za IL-28B pokazala je da su 335 od 595 (56,3%) ispitanika bili CT heterozigoti, 173 od 595 ispitanika (29,1%) C homozigoti i 87 od 595 ispitanika (14,6%) T homozigoti. Distribucija C i T alela u SNP-u rs12979860 gena za IL-28B sukladni su literaturnim podatcima analize prevalencije ovih alela u osoba bijele rase europskog porijekla., Single nucleotide polymorphism (SNP) rs12979860 in the promotor region of the gene coding for interleukin-28B (IL-28B) is associated with the natural history of hepatitis C virus (HCV) infection and response to antiviral and immunomodulatory therapy with combination of pegylated interferon alpha and ribavirin (dual therapy). Despite the fact that the predictive role IL-28B genotyping is decreasing in the era of highly successful direct acting antiviral (DAA)-based treatment, it remains to be useful as a tool for predicting a natural course of HCV infection. In resource-limited settings with restricted access to new treatment options IL-28B polymorphism typing is still a part of pre-treatment workup before admission of dual therapy. The aim of this study was to analyse the results of IL-28B genotyping (percentages of C and T homozygotes and heterozygotes) for 595 Caucasian patients with chronic hepatitis C receiving clinical care at the Department of Viral Hepatitis of the University Hospital for Infectious Diseases, Zagreb and Croatian Reference Center for Viral Hepatitis since January 2013 till December 2015. Detection of single nucleotide polymorphism (SNP) rs12979860 was determined by using a real-time PCR test. Analysis of rs12979860 SNP in the IL-28B gene showed that 335 of 595 (56.3%) patients were CT heterozygotes, followed by C homozygotes (173 of 595 patients, 29.1%) whereas T homozygotes were the least frequent (87 of 595 patients, 14.6%). The patterns of IL-28 polymorphism in Croatian patients with chronic hepatitis C is in accordance with other results for Caucasians.

Research and publication expenses were supported in part by the Croatian Science Foundation and PLIVA Croatia Ltd. (project no. 04/30 'Research on the aetiology, epidemiology, diagnostics, and treatment of patients with prostatitis syndrome').

HIV-positive individuals that have a detected transmitted drug resistance (TDR) at baseline have a higher risk of virological failure with antiretroviral therapy (ART). This study offers an update on the prevalence of TDR in Slovenia, looks for onward transmission of TDR, and reassesses the need for baseline drug resistance testing. Blinded questionnaires and partial pol sequences were obtained from 54.5% (168/308) of all of the patients diagnosed with HIV-1 from 2011 to 2016. Subtype B was detected in 82.7% (139/168) of patients, followed by subtype A (8.3%), subtype C (2.4%), and CRF01_AE (1.8%). Surveillance drug resistance mutations (SDRMs) were found in four individuals (2.4%), all of them men who have sex with men (MSM) and infected with subtype B. K103N was detected in two patients and T68D and T215D in one person each, corresponding to a prevalence of 0%, 1.2%, and 1.2% of TDR to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs), respectively. The impact of mutations on drug susceptibility was found to be most pronounced for NNRTIs. No forward spread of TDR within the country was observed; however, phylogenetic analysis revealed several new introductions of HIV into Slovenia in recent years, possibly due to increased risky behavior by MSM. This was indirectly confirmed by a substantial increase in syphilis cases and HIV-1 non-B subtypes during the study period. A drug-resistant HIV variant with good transmission fitness is thus more likely to be imported into Slovenia in the near future, and so TDR should be closely monitored.

BACKGROUND: Standardized and validated methods for the specific detection and identification of a spectrum of high-risk (hr) HPV genotypes will be necessary if HPV genotyping gains an important role in the clinical management of HPV-related precancerous lesions and cancers. OBJECTIVES: The first comparative evaluation of novel HPV genotyping Digene HPV Genotyping RH Test RUO (Qiagen, Hilden, Germany) with standard INNO-LiPA HPV Genotyping Extra CE assay (Innogenetics, Gent, Belgium). STUDY DESIGN: Seventy hr-HPV positive samples were tested in parallel with both genotyping assays. The results were interpreted taking into account 15 hr-HPV and 3 probable hr-HPV genotypes that can be identified by both assays (assay-common genotypes). RESULTS: Concordant results (a complete match of assay-common genotypes or negative using both assays) and compatible results (at least one genotype in common) were obtained in 42 (60.0%) and 28 (40.0%) samples, respectively. No discordant results for assay-common genotypes were obtained. Of 42 samples with compatible results, the presence of at least one assay-common genotype was detected in 37 samples, while no HPV was detected in two samples by both assays and only a single low-risk HPV was detected by INNO-LiPA in three samples. CONCLUSIONS: A novel Digene test is suitable for the detection of hr-HPV genotypes in clinical samples and it provides comparable results to the well established INNO-LiPA assay. Although INNO-LiPA identified significantly more samples with multiple HPV genotypes than the Digene test, the clinical benefit of such a difference is at present unclear.

Prometryne is a methylthio-s-triazine herbicide. Significant traces are documented in environment, mainly waters, soil and plants used for nutrition. The aim of this study was to estimate prometryne immunotoxic properties through induction of apoptotic and/or necrotic changes in thymocytes, splenocytes and lymph node cells after repeated subchronical exposure. Three different doses of prometryne (185, 375, 555mgkg(-1)) were applied per os every 48h, over 28 days. Flow cytometry assay (annexinV-FITC and PI) was conducted to record apoptotic and necrotic damage. In the spleen significant changes in the percentage of apoptotic cells were not detected between treated and control groups respectively. In thymus and lymph node, within the lowest dose group (185mgkg(-)1), an increase in percentage of early apoptosis without any significant increase in necrosis was detected. Medium (375mgkg(-1)) as well as high dose triggered increase in late apoptosis in lymph node while in thymus; late apoptosis was increased only in animals exposed to the highest dose (555mgkg(-1)). The highest applied dose, in thymus and lymph node respectively, caused a general decrease in percentage of vital cells in favour of marked increase of percentages of all types of dying cells (apoptotic, late apoptotic/early necrotic and necrotic). Prometryne caused disbalance in major organs of immune system, markedly lymph nodes and thymus, by induction of early apoptotic changes in dose/time specific manner.

There are limited data on how HIV prevention interventions affect individuals presenting to care in settings with a low-level HIV epidemic. We examined whether interventions undertaken during the Croatian Global Fund Project in 2004-2006 had an influence on patients entering care. The number of men who have sex with men (MSM) presenting in 2004-2006 (n = 86) was 59% higher than in 2001-2003 (n = 54) ; in heterosexual patients the increase was 14% (n = 51 in 2001-2003 ; n = 58 in 2004-2006). MSM presented at a younger age (median 32 years) in 2004-2006 than in 2001-2003 (median 36 years). Late presentation to care was found in 28% of MSM and in 59% of heterosexual patients in 2004-2006. MSM were less frequently late presenters in 2004-2006 compared with 2001-2003 (odds ratio, 0.48 ; 95% confidence interval, 0.24 to 0.99 ; P = 0.046). Additional strategies for earlier initiation of care must be developed for MSM and particularly for heterosexual patients.

OBJECTIVES: The aim of our study was to determine whether cerebrospinal fluid (CSF) of patients with tick-borne encephalitis (TBE) contains CXCL10, CXCL11, p40 subunit of interleukin-12 (IL-12)/IL-23, IL-18 and IL-15. We compared serum and CSF concentrations of CXCL10 and analysed the possible concentration gradient of this chemokine between the periphery and central nervous system. ----- MATERIALS AND METHODS: The study enrolled 19 TBE patients and 10 patients with non-inflammatory neurological diseases. ----- RESULTS: CSF of TBE patients contained CXCL10 (median 217 pg/ml), CXCL11 (8.3 pg/ml), p40 subunit of IL-12/IL-23 (38.9 pg/ml), IL-18 (30.1 pg/ml) and IL-15 (5.9 pg/ml). CXCL10 in the CSF of TBE patients was higher compared with serum (median 62 pg/ml, P < 0.001). ----- CONCLUSION: CSF of TBE patients contains CXCL10, CXCL11, p40 subunit of IL-12/IL-23, IL-18 and IL-15. Increased CXCL10 concentration in CSF suggests a role for this chemokine in the recruitment of CXCR3-expressing T-cells into the CSF of TBE patients.

Problem: Data given in the literature, regarding the influence of antisperm antibodies (ASA) in the semen and/or sera on in vitro fertilization (IVF) procedure outcome are controversial. The aim of this study was to compare the prevalence of ASA in semen, peripheral blood and follicular fluid as well as to determine total immunoglobulin concentration in the serum and follicular fluid. Selected parameters were analyzed with regard to IVF outcome. Method of study: The study enrolled 52 married couples. ASA in the semen was determined by direct immunobead mixed antiglobulin reaction (MAR Screen test), while in the peripheral blood and follicular fluid was determined by indirect immunobead MAR Screen test. Immunoglobulin (IgG, IgM and IgA) concentration in the follicular fluid and serum was determined by a liquid-phase immunoprecipitation assay with nephelometric end-point detection and analyzed with regard to IVF outcome. Results: Semen MAR test IgG was 20% in 14 couples. Fertilization (73.2% versus 71.5%) and pregnancy rates (28.9% versus 28.57%) in both groups of patients were not significantly different. The results of direct and indirect MAR test were not associated with fertilization and pregnancy rates. Total serum IgG, IgM and IgA in infertile women were within normal ranges. Follicular fluid IgG was within normal values for serum samples, while IgA and IgM were decreased. Conclusion: The presence of ASA on sperm or in the serum and follicular fluid was not associated with IVF outcome in the couples with good quality semen characteristic.

Problem: To analyse percentage of total and memory CD27+ B-cells and other lymphocyte subpopulations in the peripheral blood (PB) and follicular fluid (FF) of infertile married couples. Method of study: Forty-eight couples from in vitro fertilization/embryo transfer (IVF/ET) programme were divided into four groups: patients with previous unsuccessful fertilization (n = 13), ectopic pregnancy (n = 8), multiple (at least three) failed IVF/ET (n = 18) and missed abortions (n = 9). Control group consisted of 15 married couples with healthy children. Results: PB memory CD27+ B-cells were significantly decreased in all groups of infertile patients compared with controls. First group had increased memory B-cells percentages compared with the second group. The differences in the percentages of PB memory B-cells in third and fourth group compared with the first group were not statistically significant. FF memory B-cells in the first and third group were significantly increased compared with second and fourth group. The percentage of total FF B-cells in all groups were significantly decreased compared with their percentage in PB. Male partners of women from the first group had had significantly increased percentages of memory B-cells compared with the partners of women from the second group. Percentage of total T- and B-cells, CD4+ and CD8+ T-cells, NK cells and activated HLA-DR+ T-cells in all groups were not significantly different from controls. We found no statistically significant difference between immunoglobulin E levels in all groups of patients. We found lower levels of IgA and IgM in FF compared with serum in all groups. Conclusion: Infertile patients have significantly decreased percentage of CD27+ B-cells in the PB. Abnormalities in the memory B-cell compartment may contribute to the pathogenesis of infertility. In the T-cell compartment abnormalities were not detected. It appears that hormonal stimulation did not influence cellular immunity parameters.

Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution. Fil: Jelen, Mateja M. University of Ljubljana; Eslovenia Fil: Chen, Zigui. Albert Einstein College of Medicine. New York; Estados Unidos Fil: Kocjan, Botjan J.. University of Ljubljana; Eslovenia Fil: Burt, Felicity J.. University of the Free State. Bloemfontein; Sudáfrica Fil: Chan, Paul K.S.. Chinese University of Hong Kong; China Fil: Chouhy, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Combrinck, Catharina E.. University of the Free State. Bloemfontein; Sudáfrica Fil: Coutlee, Francois. Hôpital Notre-Dame-Pavillon Deschamps. Montréal; Canadá Fil: Estrade, Christine. Lausanne University Hospital; Suiza Fil: Ferenczy, Alex. McGill University and Jewish General Hospital. Montreal; Canadá Fil: Fiander, Alison. Institute of Cancer and Genetics. Cardiff; Reino Unido Fil: Franco, Eduardo L.. McGill University. Montreal; Canadá Fil: Garland, Suzanne M.. The Royal Women's Hospital. Parkville; Australia. The University of Melbourne; Australia. Murdoch Children's Research Institute. Victoria; Australia Fil: Giri, Adriana Angelica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: González, Joaquín Víctor. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina Fil: Gröning, Arndt. Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH. Hannover; Alemania Fil: Heidrich, Kerstin. Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH. Hannover; Alemania Fil: Hibbitts, Sam. Institute of Cancer and Genetics. Cardiff; Reino Unido Fil: Hosnjak, Lea. University of Ljubljana; Eslovenia Fil: Luk, Tommy N.M. The Chinese University of Hong Kong; China. Hong Kong Special Administrative Region; China Fil: Marinic, Karina. Hospital Dr. Julio C. Perrando. Chaco; Argentina Fil: Matsukura, Toshihiko. National Institute of Health. Tokyo; Japón Fil: Neumann, Anna. The University of Melbourne; Australia. Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH. Hannover; Alemania Fil: Oštrbenk, Anja. University of Ljubljana; Eslovenia Fil: Picconi, Maria Alejandra. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina Fil: Richardson, Harriet. Queen's University. Ontario; Canadá Fil: Sagadin, Martin. University of Ljubljana; Eslovenia Fil: Sahli, Roland. Lausanne University Hospital; Suiza Fil: Seedat, Riaz Y.. University of the Free State. Bloemfontein; Sudáfrica Fil: Seme, Katja. University of Ljubljana; Eslovenia Fil: Severini, Alberto. Public Health Agency of Canada. Winnipeg; Canadá Fil: Sinchi, Jessica L. Hospital Dr. Julio C. Perrando. Chaco; Argentina Fil: Smahelova, Jana. Institute of Hematology and Blood Transfusion. Praga; República Checa Fil: Tabrizi, Sepehr N.. The University of Melbourne; Australia. Murdoch Children's Research Institute. Victoria; Australia. The Royal Women's Hospital. Parkville; Australia Fil: Tachezy, Ruth. Institute of Hematology and Blood Transfusion. Praga; República Checa Fil: Tohme, Sarah. Public Health Agency of Canada. Winnipeg; Canadá Fil: Uloza, Virgilijus. Lithuanian University of Health Sciences. Kaunas; Lituania Fil: Vitkauskiene, Astra. Lithuanian University of Health Sciences. Kaunas; Lituania Fil: Wong, Yong Wee. Universti Kebangsaan Malaysia. Bangi; Malasia Fil: Lepeja, Snježana Židovec. University Hospital for Infectious Diseases Dr. Fran Mihaljević. Zagreb; Croacia Fil: Burk, Robert D.. Albert Einstein College of Medicine.New York; Estados Unidos Fil: Poljak, Mario. Albert Einstein College of Medicine. New York; Estados Unidos

Opisali smo glavne novosti u dijagnostici hepatitisa B i C kao dio hrvatskih smjernica za dijagnostiku i liječenje virusnih hepatitisa 2013. Dijagnostika akutnog i kroničnog hepatitisa B započinje određivanjem HBsAg, anti-HBc i anti-HBs. Ostale serološke biljege hepatitisa B treba određivati tek u drugom koraku ako su nalazi HBsAg i/ili anti-HBc pozitivni. Pozitivan nalaz samo na anti-HBc potrebno je obvezno nadopuniti određivanjem HBV DNK. Kvantitativno određivanje HBsAg treba se koristiti komplementarno s određivanjem HBV DNK za: (i) razlikovanje inaktivnog nositelja HBsAg od aktivnog kroničnog HBeAg-negativnog hepatitisa B u bolesnika sa HBV DNK nižom od 2.000 IU/mL te za (ii) praćenje tijeka liječenja kroničnog hepatitisa B s pegiliranim interferonom-alfa. Metoda PCR-a u stvarnom vremenu ostaje i dalje metoda izbora za detekciju i kvantifikaciju HBV DNK. Testiranje za HCV započinje određivanjem specifičnih protutijela probirnim enzimskim imunotestovima ili brzim testovima. Sve osobe s pozitivnim probirnim anti-HCV testom treba testirati na prisutnost HCV RNK ili antigena virusne kapside. Potvrdne anti-HCV testove treba koristiti samo kao dodatne testove koji će potvrditi ili isključiti značenje reaktivnih rezultata probirnih enzimskih imunotestova u osoba koje su HCV RNK negativne. U praćenju virusne kinetike tijekom trojne terapije hepatitisa C preporučuje se korištenje molekularnih testova s identičnom donjom granicom detekcije (LLOD) te donjom granicom kvantifikacije. Određivanje rezistencije HCV-a na inhibitore proteaze nije dio obveznog dijagnostičkog praćenja bolesnika liječenih s trojnom terapijom. Ne postoje dostatni dokazi o potrebi uvođenja subtipizacije HCV-a u obveznu predterapijsku obradu bolesnika s kroničnim hepatitisom C. Genotip IL-28 je važan prediktor SVR-a u bolesnika liječenih kombinacijom IFN i ribavirina kao i u bolesnika zaraženih genotipom 1 liječenih trojnom terapijom. Genotipizacija IL-28B preporučuje se u predterapijskoj obradi bolesnika s kroničnim hepatitisom C. Posebno je značajan dijagnostički parametar u terapijski-naivnih bolesnika s kroničnim hepatitisom C prilikom dvojbe dvojna vs. trojna terapija., The 2013 Update of the Croatian Guidelines for the Diagnosis and Treatment of Viral Hepatitis summarizes recent developments in the diagnosis of hepatitis B and C. Determination of HBsAg, anti-HBc and anti-HBs is the initial step in the diagnostic workup of acute and chronic hepatitis B. Other hepatitis B serologic markers should be analyzed in the second stage of the diagnostic workup in HBsAg and/or anti-HBc positive patients. A positive anti-HBc finding should be followed by HBV DNA quantification. HBsAg quantification is complimentary to the HBV DNA quantification and is used: (i) to differentiate between inactive HBsAg carriers and active chronic HBeAg-negative hepatitis B in patients with HBV DNA

Hrvatske konsenzus konferencije o virusnim hepatitisima održane su 2005. i 2009. g. (1). S obzirom na brojne nove spoznaje o epidemiologiji, dijagnostici i liječenju virusnih hepatitisa (poglavito kroničnog hepatitisa C genotipa 1) u protekle četiri godine, 28. veljače 2013. g. održana je nova Hrvatska konsensus konferencija o virusnim hepatitisima u Zagrebu. Sažeti tekst ove Hrvatske konsenzus konferencije o virusnim hepatitisima sadrži prikaz novih spoznaja o epidemiologiji virusnih hepatitisa, serološkoj i mo¬lekularnoj dijagnostici virusnih hepatitisa, određivanju polimorfizma promotora gena za IL-28, procjeni stadija fibroze, algoritmu dijagnostičkog praćenja bolesnika, liječenju kroničnog hepatitisa C (genotipovi 1-6) i hepatitisa B, liječenju specijalnih populacija (djeca, bolesnici na dijalizi, bolesnici liječeni transplantacijom, osobe s HIV/HCV koinfekcijom) i nuspojavama liječenja., 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, fi¬brosis grading, algorithm for patient diagnostic follow up, treatment of chronic hepatitis C (genotypes 1-6) and hepatitis B, treat¬ment of special populations (children, dialysis patients, transplanted patients, individuals with HIV/HCV co-infection), and therapy side effects.

Trajni virusološki odgovor nakon 48 tjedana liječenja kombinacijom pegiliranog interferona alfa-2 i ribavirina u bolesnika s kroničnim hepatitisom C inficiranih genotipom 1 postiže se u oko 55% bolesnika. Prethodne studije pokazale su da je kraća, 24-tjedna terapija u bolesnika s niskom početnom viremijom (, About 55% of patients with genotype 1 chronic hepatitis C infection have sustained response to 48-week therapy with pegylated interferon alfa-2 and ribavirin. Previous studies have shown that patients with low pretreatment viremia (< 600 000 IU/mL) can be treated for 24 weeks with similar efficacy as with 48-week therapy, when early viral kinetic is measured. Our study showed that patients with low pretreatment viral load (< 600 000 IU/mL) are very heterogenous group and sustained viral response to pegylated interferon alfa-2 and ribavirin therapy is not better than in high viral load group (low viremia patients SVR 53.2% (n = 94), high viremia patients SVR 50.8% (n = 122)). Pretreatment low viral load patients that did not achieve SVR (n = 44) had a significantly higher fibrosis stage (non-SVR fibrosis stage 3.47 Ishak score vs. SVR+ fibrosis stage 2.94; p = 0,004), and they were significantly older (non-SVR patients 46.4 years, SVR+ patients 39.6 years, p = 0.008). Low initial viremia patients with cirrhosis (n = 6) did not achieve SVR at all, while among patients with fibrosis stage 4/6, 52 % achieved SVR. Our results suggest that apart from viral load at the beginning of treatment, fibrosis stage is also a predicting factor for therapy outcome, particularly in older patients and patients with cirrhosis.

Cilj ovog istraživanja bio je odrediti heterogenost podtipova HIV-a te analizirati primarnu rezistenciju virusa na antiretrovirusne lijekove u 30 prethodno neliječenih osoba koje su uključene u kliničku skrb Referentnog centra za dijagnostiku i liječenje HIV/AIDS-a tijekom 2013. g. Sekvenciranjem pol gena HIV-a te primjenom bioinformatičkih algoritama određeni su podtipovi virusa te detektirane mutacije povezane s primarnom rezistencijom na antiretrovirusne lijekove. Većina ispitanika (86,7%) bila je zaražena podtipom B. Otkriveno je 12 mutacija povezanih s primarnom rezistencijom HIV-a na antiretrovirusne lijekove, tj. 9 mutacija povezanih s primarnom rezistencijom na nukleozidne analoge inhibitore reverzne transkriptaze (NRTI) te 3 mutacije povezane s rezistencijom na nenukleozidne inihibitore reverzne transkriptaze (NNRTI). Primarna rezistencija na dvije klase antiretrovirusnih lijekova (NRTI i NNRTI) otkrivena je u jednog ispitanika. Najzastupljenija mutacija povezana s primarnom rezistencijom virusa na lijekove bila je T215S (rezistencija na NRTI). Mutacije značajne za nastanak primarne rezistencije detektirane su u 4 osobe zaražene podtipom B, jedne osobe zaražene podtipom A1 te jedne osobe zaražene rekombinantom podtipova A1 i B. U ovom je istraživanju po prvi puta dokazana pojava primarne rezistencije HIV-a na antiretrovirusne lijekove u osoba zaraženih non-B podtipovima virusa iz Hrvatske., The aim of this study was to analyse HIV subtype diversity as well as primary resistance to antiretroviral drugs in 30 treatment-naive individuals entering clinical care at the National Refence Center for HIV/AIDS during 2013. Sequencing the pol region of the viral genome and bioinformatic algorithms were used to determine HIV subtypes and to analyse transmitted drug resistance mutations. The majority of individuals (86,7 %) were infected with HIV-1 subtype B. Twelve mutations associated with primary resistance to antiretroviral drugs were detected in the study: 9 mutations conferring resistance to NRTI (nucleotide reverse-transcriptase inhibitors) and 3 mutations associated with resistance to NNRTI (non-nucleotide reverse-transcriptase inhibitors). Primary resistance to two antiretroviral drug classes (NRTI and NNRTI) were detected in one individual. The most frequent mutation was T1215S associated with primary resistance to NRTI. Drug resistance mutations were detected in 4 subtype B and 2 non-B HIV-infected individuals. This study showed, for the first time, the presence of mutations associated with primary resistance of HIV to antiretroviral drugs in individuals infected with non-B subtypes in Croatia.

Background We assessed the feasibility of collecting urine samples for testing on genital Chlamydia trachomatis infection in a population-based survey, and prevalence of this infection among young people aged 18-25 in Croatia. In Croatia, as in the other countries of Eastern Europe, there is a lack of data on prevalence of C trachomatis in the general population, including young adults. Methods We sampled participants using a nationally representative, multi-stage stratified probability sample of young men and women. Detection of C trachomatis DNA in urine samples was performed by using a real-time PCR assay COBAS® TaqMan® CT Test, v2.0. Results Overall, 1005 young adults participated in the behavioural part of the survey, and 27.9% men and 37.5% women who were sexually experienced agreed to provide urine samples for testing on C trachomatis. Using multivariate analysis, women were significantly more likely to provide urine samples than men (aOR = 1.53, 95% CI 1.14-2.06) as were those who reported no condom use at last intercourse (aOR = 1.95, 95% CI 1.44-2.62). Prevalence of C trachomatis infection among those who were sexually experienced was 7.3% in men and 5.3% in women. Conclusions Population-based surveys that use probabilistic sampling are a feasible way to obtain population estimates of C trachomatis prevalence among young adults in Croatia, but it is challenging to obtain an adequate response rate. The prevalence of C trachomatis among young adults in Croatia found in this study was higher than that found in other European countries with similar survey response rates.

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