Significance of UGT1A1*28 Genotype in Patients with Advanced Liver Injury Caused By Chronic Hepatitis C.

BACKGROUND: Chronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations in UGT1A1 gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association of UGT1A1 TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse. METHODS: Genetic testing of UGT1A1 TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging. RESULTS: UGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence of UGT1A1*28 genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation of UGT1A1*28 genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence of UGT1A1*28 genotype in CHC patients with severe liver injury. CONCLUSIONS: Frequencies of UGT1A1*28 genotype are high in both Serbian CHC patients and healthy subjects. The presence of UGT1A1*28 genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.

IL-28B genotypes as predictors of long-term outcome in patients with hepatitis C-related severe liver injury.

INTRODUCTION: Patients with severe fibrosis or cirrhosis are at high risk for liver-related complications, even after successful antiviral treatment and/or regression of fibrosis. These are the first published results concerning the role of IL-28B genotypes as predictors of the durability of sustained virological response (SVR) and long-term outcome, in patients with baseline severe fibrosis and cirrhosis caused by hepatitis C (HCV) infection. METHODOLOGY: Genetic testing for three different single nucleotide polymorphisms (SNP) near the IL28B gene, rs12979860, rs12980275 and rs8099917, was performed in 42 patients with HCV-related advanced fibrosis and cirrhosis, who achieved SVR after successful interferon-based treatment. Baseline clinical and laboratory parameters were analysed, as well as IL28B genotype association with late virological relapse, fibrosis progression and clinical outcomes. RESULTS: The most prevalent genotypes in all three tested SNP positions were: CCrs12979860 genotype in 69% of patients, GTrs8099917 in 78.6% and GGrs12980275 in 47.6% of patients. The presence of IL28B CCrs12979860 genotype was identified as a negative predictor of late virological relapse. Further analysis did not confirm the association of other IL28B genotypes with the progression of fibrosis and clinical outcomes. CONCLUSIONS: Varying long-term prognosis in patients with HCV-related severe fibrosis and cirrhosis is due to multiple interactions between host genetic factors, virus and environment. These are first published results demonstrating the significance of IL28B CCrs12979860 genotype as a negative predictor of late virological relapse. A further investigation concerning genetic factors is necessary to identify patients under risk for late relapse, complications and unfavorable outcomes, so that they can be reevaluated and offered new treatment options.

The prevalence and the risk factors for hepatitis C virus infection in Serbia.

INTRODUCTION: The epidemiological characteristics of the hepatitis C virus (HCV) infection in Republic of Serbia have not been studied sufficiently so far. The aim of this study was to estimate the prevalence of anti-HCV positivity in the general population of Serbia and determine the risk factors for this infection. METHODOLOGY: Estimation of the prevalence was done using the median ratio method with data from several regional countries to a previously determined prevalence of anti-HCV positivity among volunteer blood donors of 0.19%. In order to determine the risk factors a matched case-control study was conducted of 106 subjects with confirmed HCV infection from the Clinic for Infectious and Tropical Diseases, Clinical Center of Serbia and the same number of hospital controls matched by sex and age. RESULTS: The estimated prevalence of anti-HCV positivity in the general population of Serbia was 1.13% (95% CI: 1.0-1.26%). The most important predictive risk factors of HCV infection were: intravenous drug use (OR = 31.0; 95% CI: 3.7-259.6), blood transfusions (OR = 3.7; 95% CI: 1.6-8.7), invasive dental treatment (OR = 3.1; 95% CI: 1.4-6.8), and low level of education (OR = 2.2; 95% CI:1.1-4.7). A total of 91.5% of the persons with hepatitis C had at least one of the significant risk factors. CONCLUSION: The prevalence of anti-HCV positivity ranks Serbia in the range of mid-endemic European countries. Preventive measures should be directed at preventing drug use, on education about getting the infection, creating safe conditions for blood transfusions, and strict adherence to adopted practices in dentistry.

ANTIVIRAL TREATMENT OF HEPATITIS C IN SERBIAN PRISON SETTING: MEDICAL TREATMENT OUTCOMES AND PATIENTS' ADHERENCE.

INTRODUCTION: Seroprevlence of chronic hepatitis C viral infection in correctional facilities ranges from 16% to 49%. However, there are only very limited data available on the course of hepatitis C viral infection and outcomes oftreatment with pegylated interferon plus ribavirin in correctional settings. The aim ofthis study was to assess the feasibility and effectiveness of use of pegylated interferon plus ribavirin treatment in the Serbian correctional setting. MATERIAL AND METHODS: The study sample consisted of the patients with hepatitis C hospitalized in the Special Hospital for Prisoners in Belgrade (Serbia) during 2007-2013. Health authorities approved treatment for 32 patients out of 76 treatment-naive patients referred to this institution. The patients (N=32) received 180 mcg pegylated interferon alfa-2a once a week plus oral ribavirin in dosage of 800 mg or 1000/1200 mg/day for 24 or 48-week treatment. All patients who completed therapy were assessed at the end of an additional 24-week treatment-free period for a sustained virological response. RESULTS: Sustained virological response was achieved in 53.8% of hepatitis C viral infection genotype I patients and in 73.3% and 66.6% of patients with hepatitis C viral infection genotype 3 and 4, respectively. One patient with mixed genotype (1, 2) did not achieve sustained virological response. The overall safety profile of the treatment regimen was very good. The incidence of influenza-like symptoms and depression were low A serious adverse event was recorded only in 6.4% of patients. CONCLUSION: The results showed that pegylated interferon alfa-2a plus ribavirin given once a week was well tolerated among prisoners and the regimen had the same adherence and effectiveness as in general population.

The Importance of Haematological and Biochemical Findings in Patients with West Nile Virus Neuroinvasive Disease.

BACKGROUND: West Nile virus neuroinvasive disease (WNND) occurs in less than 1% of infected people. Leukocytosis with lymphocytopenia, mild anaemia, thrombocytopenia, elevated liver and muscle enzymes and hyponatremia are occasionally present in patients with WNND. Cerebrospinal fluid (CSF) findings resemble other viral neuroinfections. The purpose of this study is to pre sent some of the most important laboratory findings of our patients with WNND and to evaluate their correlation with fatal outcome. METHODS: The study included 161 patients with WNND. Their blood and CSF samples were cytobiochemically analysed and the obtained variables were then tested for predictive significance of the disease outcome, or used for differentiation between two clinical syndromes (encephalitis vs meningitis). RESULTS: West Nile encephalitis was present in 127 (78.9%) patients and West Nile meningitis was diagnosed in 34 (21.1%) cases. Leukocytosis was found in 45.9% patients. CRP level higher than 100 mg/L was registered only in those with encephalitis (p=0.020). CSF leukocyte count was 146±171 per microlitre, with slight lymphocytic predominance (mean 52%). Hypoglycorrhachia was registered in 9.3% of our patients with WNND. Twenty-eight (17.4%) patients died and all of them had encephalitis. Independent predictors of fatal outcome in WNND were serum CRP > 100 mg/L (p=0.011) and CSF proteins > 1 g/L (p=0.002). CONCLUSIONS: WNND usually affects older males. Prolonged neutrophilic predominance in CSF can occasionally be present, as well as hypoglycorrhachia. Patients with encephalitis, high serum CRP and high CSF protein level have a higher risk of fatal outcome.

Oral teicoplanin for successful treatment of severe refractory Clostridium difficile infection.

INTRODUCTION: Clostridium difficile is the leading cause of hospital-acquired diarrhoea. There is no defined protocol for treating severe Clostridium difficile infection (CDI) refractory to vancomycin or vancomycin and metronidazole combination therapy. The aim of this study was to evaluate the rate of clinical cure, time to resolution of diarrhoea and recurrence rate in patients with severe refractory CDI treated with oral teicoplanin. METHODOLOGY: A one-year prospective study was carried out in the Clinic for Infectious and Tropical Diseases, Clinical Center Serbia. Patients with severe and complicated CDI who failed to respond to oral vancomycin and intravenous metronidazole combination therapy were enrolled. They were given oral teicoplanin 100 mg bi-daily. Patients were followed for recurrence for eight weeks. RESULTS: Nine patients with a mean age of 70.8±9.4 years were analyzed. All patients had pseudomembranous colitis, and five had complicated disease. In four patients intracolonic delivery of vancomycin was also performed in addition to oral vancomycin and intravenous metronidazole prior to initiating teicoplanin, but without improvement. After teicoplanin initiation all patients achieved clinical cure. The mean time to resolution of diarrhoea after teicoplanin introduction was 6.3±4.5 days. There was no statistically significant difference in time to resolution of diarrhoea according to initial leucocyte count, age over 65 years, the presence of ileus, complicated disease and the use of concomitant antibiotic therapy (p = 0.652, 0,652, 0.374, 0.374, and 0,548, respectively). None of the patients experienced recurrence. CONCLUSIONS: Oral teicoplanin might be a potential treatment for severe and complicated refractory CDI, but further studies are required.

Seroprevalence and risk factors for hepatitis C virus infection among blood donors in Serbia: A multicentre study.

BACKGROUND: The epidemiological characteristics of hepatitis C virus (HCV) infection have not yet been described in Serbia. AIMS: To determine the prevalence of anti-HCV-positive individuals among first-time blood donors and the risk factors for hepatitis C transmission. METHODS: A multicentre case-control study nested within a prospective cohort study was conducted at 10 main transfusion centres in Serbia in 2013 and 27,160 blood donors who gave blood for the first time were included. Blood donors with confirmed anti-HCV positivity and seronegative controls were enrolled to determine the risk factors. RESULTS: Of 27,160 blood donors 52 were anti-HCV-positive; seroprevalence was 0.19%. By univariate analysis, marital status, educational level, drug use, previous transfusion, tattooing, non-use of condoms and number of sexual partners, were risk factors for hepatitis C. In the final multivariate analysis, three factors remained independently predictive: drug use, tattooing and previous blood transfusion. In total, 87.5% of cases had at least one of the risk factors for HCV transmission; 20.9% presumed that they knew when the infection occurred. CONCLUSION: HCV seroprevalence in Serbia is higher than in developed European countries. Preventive measures need to be directed towards drug use and tattooing facilities. The admission questionnaire for blood donors should be improved.

A tool for selecting patients with a high probability of sustained virological response to peginterferon alfa-2a (40kD)/ribavirin.

BACKGROUND & AIMS: Pretreatment identification of patients likely to achieve a sustained virological response (SVR) with peginterferon alfa-2a/ribavirin would be useful for individualizing treatment choices. The aim of this analysis was to devise a simple scoring system to identify patients with high probability of achieving an SVR with peginterferon alfa-2a/ribavirin. METHODS: Using data from 2109 Caucasian treatment-naive hepatitis C virus (HCV) genotype 1 mono-infected patients from the PROPHESYS cohorts, the relationship between favourable baseline characteristics and SVR was explored using generalized additive model analysis, and a scoring system was devised to predict SVR. RESULTS: Points were assigned for: age (years) (≤35: 2; >35, ≤45: 1; >45: 0); body mass index (kg/m(2)) (≤20: 2; >20, ≤22: 1; >22: 0); HCV RNA (IU/ml) (≤100,000: 3; >100,000-400,000: 2; >400,000-800,000: 1; >800,000: 0); platelets (>150 ×10(9)/l: 1; ≤150 ×10(9)/l: 0); alanine aminotransferase [×upper limit of normal (ULN)] (>3: 1; ≤3: 0); serum aspartate aminotransferase (×ULN) (≤1: 1; >1: 0). 1029, 698 and 382 patients had scores of 0-2, 3-4 and ≥5, respectively, among whom SVR rates were 35.0, 54.9 and 76.7%. SVR in patients with scores ≥5 and undetectable HCV RNA by week 4 was 86.7%. The score was tested against two databases of patients who received peginterferon alfa-2a/ribavirin in other clinical trials; similar high SVR rates in patients with scores ≥5 were reported. CONCLUSIONS: The scoring system can reliably identify treatment-naive HCV genotype 1 mono-infected Caucasian patients who have a high probability of achieving an SVR with peginterferon alfa-2a/ribavirin and will be particularly useful where protease inhibitors are not readily available.

[Importance of adherence for efficacy of hepatitis C combined therapy].

INTRODUCTION: Dual antiviral therapy with pegylated interferon alfa-2a and ribavirin leads do sustained elimination of hepatitis C virus infection in over 50% patients with genotypes 1 and 4 and in over 80% with genotypes 2 and 3. In addition to genotype, for predicting success of therapy, important factors are baseline HCV RNA level, age, sex, stage of fibrosis, insulin resistance, degree of fat in liver, and patient's weight and genetics. Also, adherence to therapy could be a very important factor associated with success of therapy. OBJECTIVE: The aim of this study was to assess importance of therapy adherence and reduced doses of pegylated interferon alfa-2a and ribavirin on sustained virological response. METHODS: One hundred and sixteen patients with chronic hepatitis C were analyzed. Sustained virological response was analyzed in relation to whether the patients received a full cumulative dose of pegylated interferon alfa-2a, a full cumulative dose of pegylated interferon alfa-2a and ribavirin, and a full cumulative dose of pegylated interferon alfa-2a and at least 60% the expected cumulative dose of ribavirin. RESULTS: At the end of the follow-up period, sustained virological response was achieved in 26 (96.3%) patients who received full cumulative dose of pegylated interferon alfa-2a and in 66 (74.2%) who did not (p < 0.05). Sustained virological response was achieved in 18 (94.7%) patients who received full cumulative dose of pegylated inteferon alfa-2a and ribavirin, and in 73 (76%) who did not (p < 0.05). Sustained virological response was achieved in 25 (96.2%) patients who received full cumulative dose of pegylated inteferon alfa-2a and at least 60% of cumulative dose of ribavirin and in 66 (74.2%) who did not (p < 0.05). CONCLUSION: These findings indicate that adherence to therapy for chronic hepatitis C is a very important factor for achieving sustained virological response.

The significance of hepatitis B virus (HBV) genotypes for the disease and treatment outcome among patients with chronic hepatitis B in Serbia.

BACKGROUND: Hepatitis B virus (HBV) genotypes influence disease progression and treatment outcome. OBJECTIVES: To determine natural history and treatment outcome in patient chronically infected with HBV. STUDY DESIGN: A cohort study included 162 treatment naive patients with chronic HBV infection in order to analyze factors influencing natural history of infection and survival. RESULTS: Genotype A was far less prevalent, detected in 14.2%. The prevalence of HbeAg+ serology of 60.8% among patients infected with genotype A was significantly higher then 30.9% recorded among those with genotype D (P=0.02). Even though patients from two genotypes subgroups had significantly different prevalence of HBeAg serology, their viral loads were similar at the time of diagnosis (2.90 log10 and 3.31 log10 HBV DNK IU/µl plasma, for genotypes A and D, respectively). The analyses of viral loads across three serologic patterns of chronic HBV infection were: for HBeAg+/HBeAb-, HbeAg-/HBAb+, and both "e" antigen and antibodies negative: 4.24, 2.67 and 2.69 log10 IU/ml of HBV DNA IU/µl, respectively (P=0.01). Mean time to liver cirrhosis was 23.2±3.4 years and 15.1±8.4 years, for genotypes A and D, respectively (P=0.02). The overall estimated mean survival of patients with chronic HBV infection was 28.4 years, and was influenced by the stage of liver disease, but not by gender, age above 40, viral genotype and lamivudine therapy. CONCLUSIONS: Patients infected with genotype D had more rapid progression to ESLD regardless of levels of viral replication. All clinical and laboratory differences between genotypes did not affect survival of patients with chronic hepatitis B, regardless of lamivudine therapy.

The influence of single and combined IL28B polymorphisms on response to treatment of chronic hepatitis C.

BACKGROUND: Three single nucleotide polymorphisms (SNPs) near IL28B gene were shown to be highly predictive of sustained virological response (SVR) in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVES: This study attempted to demonstrate the role of single and combined IL28B polymorphisms (rs8099917, rs12979860 and rs12980275) and other host and viral factors in predicting response to treatment, in Caucasian patients infected with HCV genotype 1. STUDY DESIGN: The IL28B genotypes at 3 SNPs were determined in 106 patients who underwent standard 48-week therapy and out of which 55.7% achieved SVR. RESULTS: Patients carrying genotypes CCrs12979860 or AArs12980275 were 3.5 and 3 times more likely to achieve SVR, respectively. Genotypes GGrs8099917 and TTrs12979860 were identified as predictors of treatment failure. The presence of IL28B profiles including at least one of the favourable genotypes was identified as the most important factor associated with SVR, followed by younger age and lower grade of histological activity. Of all patients who achieved SVR, 88.1% was carrying one of these IL28B profiles. The strongest PPV of single SNPs for achieving SVR was observed for CCrs12979860 (76.9%). The presence of GGrs8099917 showed the strongest NPV of 85.7%. The correlation of SNPs with other host and viral factors revealed association of TTrs8099917 and lower AST levels. CONCLUSIONS: Results of this study confirm that all investigated IL28B polymorphisms are associated with treatment response and that presence of any of the favourable IL28B genotypes can be considered independent pretreatment determinant of the effectiveness of therapy.

[Antiviral/immunomodulatory combination therapy: pegylated interferon alpha 2a and ribavirin in patients with chronic hepatitis C virus infection].

INTRODUCTION: Chronic hepatitis C virus (HCV) infection can progress to liver cirrhosis that causes bleeding from the gastrointestinal tract, liver failure and primary hepatocellular carcinoma. Use of standard therapeutic option consists of recombinant pegylated interferon alpha 2a/b with ribavirin in order to eradicate virus and prevent complications. OBJECTIVE: The aim of investigation was to evaluate efficiency of combination therapy (pegylated interferon alpha 2a/b plus ribavirin) in patients with chronic HCV infection and to estimate predictive factors for successful treatment. METHODS: A total of 387 patients with confirmed diagnosis of hepatitis C were evaluated (aged 18-65 years of both genders). Patients were treated with pegylated interferon alpha 2a/b and ribavirin according to a standard regimen lasting 24 or 48 weeks, dependent on virus genotype. RESULTS: Negative HCV RNA (PCR assay) was recorded in 79.7% of patients at the end of treatment. Six months after completed therapy, negative HCV RNA, i.e. stained virologic response (SVR) was assessed in 70.5% of patients. Statistical summary of our results concerning SVR confirmed better efficiency of combination therapy for the following parameters compared to other investigated variables: age < or = 40 (84.3% vs. 59.1%; p < 0.0005), absence of cirrhosis (75.6% vs. 58.3%; p = 0.003), lack of genotype 1 (86.6% vs. 61.8%; p < 0.0005), and in patients who received full doses of pegylated interferon alpha 2a (78.3% vs. 63.3%; p = 0.002). CONCLUSION: Combination therapy of recombinant pegylated interferon alpha 2a with ribavirin leads to SVR in the majority of treated patients (70.5%). Successful treatment depends on a variety of host and virus factors.

Depressive symptoms in patients with hepatitis C treated with pegylated interferon alpha therapy: a 24-week prospective study.

OBJECTIVE: To prospectively evaluate depressive symptoms and risk factors for depression in patients with chronic hepatitis C (CHC) treated with pegylated interferon alpha therapy combined with oral ribavirin (PEG-IFN-α+RBV) and to analyze self-rating scale for depression in comparison to observer-based scale in the given population. SUBJECTS AND METHODS: The Hamilton Depression Rating Scale and Zung Self Rating Depression Scale were used to screen for depressive symptoms in 74 subjects with CHC before PEG- IFN-α (mean dose 152.6±25.6 mcg), and in the follow-up visits (4, 12 and 24 week). RESULTS: Incidence of depressive symptoms in patients (mean age 39.9±13.4 years; equal sex distribution p=0.225) treated by PEG- IFN-α was the highest on 12th week of the treatment, when more than a 20% of our sample had moderate/severe symptoms of depression, and about 30% had minor depressive symptoms. For the screening of depression during PEG- IFN-α self-assessment scale was equally reliable as observer-based assesment of depressive symptoms. Common clinical parameters- subject related risk factors (age (p=0.955 ), sex (p=0.008), lifetime psychiatric disorder (p=0.656)), illness related risk factors (duration of CHC (p=0.267 ), i.v drug aplication as way of transmission (p=0.292)) and therapy-related risk factors (recommended duration of PEG-IFN-α (p=0.993) and dose of PEG-IFN-α (p=0.841)) were not signifcantly associated with depressive symptoms on PEG-IFN-α. CONCLUSIONS: Liason-consultation services should collaborate with hepatologists in creating screening programmes, supplemented by objective criteria and guidelines, for early recognition and treatment of interferon-induced depression.

[Influence of depression on the quality of life in patients with chronic hepatitis C].

INTRODUCTION: Chronic hepatitis C reduces the quality of life in patients causing fatigue, loss of self-confidence, reduced working capacity, development of depression, emotional problems, and cognitive dysfunction. OBJECTIVE: The aim of the study was to identify the presence of depression in patients with chronic hepatitis C, predicting factors for its expression, and the impact of depression on the quality of life in these patients. METHODS: During the prospective study, we used the Hamilton depression scale to investigate the presence of depression, generic 36-Item Short Form Health Survey (SF-36) and Chronic Liver Diseases Questionnaire (CLDQ) to examine the quality of life in 100 patients with chronic hepatitis C, 30 patients with chronic hepatitis B, 30 patients with chronic liver disease nonviral aetiology and 50 healthy persons. RESULTS: A significantly higher presence of depression, and cognitive dysfunction in patients with chronic hepatitis C were noted as compared to the healthy individuals (p=0.00). In relation to non-viral patients with chronic liver disease, depression was significantly less present (p=0.004). Depression was rare in younger patients. The largest number of patients with chronic hepatitis C was without depression. The presence of depression caused deterioration of the physical and mental components of the quality of life. Multivariate analysis showed that the most significant positive predictive factor for the presence of depression was married life (B=0.278; SE=0.094; p=0.004). CONCLUSION: The presence of depression was more often in patients with chronic hepatitis C viral infection compared to healthy population and was correlated with decline in the quality of life. Depression is more pronounced in the elderly and intravenous drug addicts. The lowest depression is expected in patients who are not married.

Characteristics of patients dying from acute viral hepatitis in Serbia.

BACKGROUND/AIMS: Acute viral hepatitis is complicated rarely with severe liver failure due to many factors associated with the etiology, patient age, and time of development of hepatic encephalopathy, etc. The aim of this study was to identify some of the clinical and laboratory features associated with a fatal outcome in patients dying from acute viral hepatitis in Serbia. METHODS: Clinical and laboratory data from 47 patients hospitalized from January 1989 December 2006 were reviewed retrospectively. Serological tests for hepatitis A, B, C, D, and E viruses, herpes simplex viruses, cytomegalovirus, and Epstein-Barr virus were done. Histological features were assessed from 35 liver tissues. The electronic base, SPSS for Windows (version 11.0), was used for statistical analysis. RESULTS: The majority of the patients had alanine aminotransferase (ALT) >20x the normal value, serum bilirubin >300 µmol/L, prothrombin time >25 seconds (s), and white blood cell count >12 x 10(9)/L. Regression analysis revealed activity of alanine aminotransferase >20x the normal value to be associated with fulminant (p=0.015) and serum bilirubin concentration with subfulminant hepatitis (p=0.008). Hepatitis B virus was the most commonly detected virus (70%). Massive hepatocyte necrosis vs. sub-massive with bridging necrosis were found to be independent of clinical presentation. CONCLUSIONS: Hepatitis B virus infection, severe impairment of liver function tests, and confluent hepatocyte necrosis and infection characterize patients dying from acute viral hepatitis in Serbia. High activity of alanine aminotransferase reflects rapid and extensive acute viral liver injury, while deep jaundice is more common in a protracted course of the disease.

[Quality of life in patients with chronic hepatitis C].

INTRODUCTION: Hepatitis C virus often causes chronic liver disease reducing physical, mental and social functions in these patients. OBJECTIVE: The aim of this investigation was analysis of the quality of life in chronic hepatitis C patients compared to patients with other chronic liver diseases and healthy population, as well as investigation of the influence of socio-demographic factors on the quality of life in patients with chronic hepatitis C. METHODS: A generic Short Form-36 (SF-36) questionnaire and Chronic Liver Diseases Questionnaire (CLDQ) were used in this prospective study for the investigation of the quality of life in 160 patients (100 patients with chronic hepatitis C, 30 patients with chronic hepatitis B, 30 patients with non-viral chronic liver diseases) and 50 healthy controls. RESULTS: Reduced quality of life was noted in patients with chronic hepatitis C patients in comparison with healthy controls (p = 0.00). Significant differences in SF-36 were found between patients with chronic hepatitis C and B regarding physical functions, activity, physical pain and emotional functions. Multivariate linear regression analysis revealed ages below 50 years as the most important positive variable in chronic hepatitis C patients for total score of the quality of life and physical component score (B = 14.5; SE = 5.16; p = 0.049; and B = 16.4; SE = 5.94; p = 0.003, respectively). The most important positive variable for the mental component of the quality of life was male gender (B = 15.3; SE = 5.81; p = 0.003). CONCLUSION: Quality of life is reduced in patients with chronic hepatitis C in comparison with healthy population. The quality of life in chronic hepatitis C patients is better than in patients with other non-viral chronic liver diseases. In comparison with patients with chronic hepatitis B, reduction in some domains of the quality of life is noted. Younger age is the most predictable group for the lowest damage of the total quality of life in patients with chronic hepatitis C patients among other sociodemographic characteristics of these patients.

[The efficacy of lamivudine in the treatment of reactivation of chronic hepatitis B virus infection in patients on immunosuppressive therapy].

INTRODUCTION: Reactivation of chronic hepatitis B virus (HBV) infection often occurs in hepatitis B surface antigen (HBsAg) positive patients undergoing immunosuppressive or chemotherapy, but can also occur in HBsAg negative, anti-HB core positive patients. Treatment of HBV reactivation with lamivudin results in favourable outcome in the majority of patients. The aim of the authors was to show the effect of lamivudin therapy to HBV reactivation caused by immunosuppressive therapy. OUTLINE OF CASES: The first patient was a 35-year-old woman with chronic hepatitis B virus infection who underwent prednisolone therapy for pulmonal sarcoidosis. Four months after the beginning of the therapy she presented with jaundice and a significant increase in serum aminotransferase level. Liver biopsy showed chronic viral B hepatitis of strong activity in the stage of rapidly developed cirrhosis. The patient was treated with lamivudine with slow reduction of prednisolone doses, which resulted in full clinical and biochemical recovery. The second patient was a 40-year-old HBsAg negative female with a previous history of resolved acute B hepatitis who received chemotherapy for non-Hodgkin lymphoma. After the third cycle of chemotherapy a significant increase in aminotransferase level occurred, chemotherapy was discontinued, but aminotransferase level still increased. At that moment she was found to be HBsAg positive, and PCR analysis detected a high viral load. Lamivudine treatment resulted in the patient's recovery and allowed further chemotherapy. CONCLUSION: In case of the reactivation of chronic HBV infection during immunosuppressive therapy, it should be stopped and antiviral therapy should be immediately initiated. The use of lamivudine results in rapid suppression of serum HBV DNA, improves the outcome and enables the continuation of immunosuppressive and chemotherapy.

Prevalence of hepatitis B virus MHR mutations and their correlation with genotypes and antiviral therapy in chronically infected patients in Serbia.

Understanding the prevalence and diversity of HBsAg variants in a population is fundamental to assay design and planning vaccination programs. It has been shown that mutations within the S gene, caused by selection or natural variation, can lead to false-negative results in assays for HBsAg, or have clinical implications, such as evading anti-HBV immunoglobulin therapy or vaccine-induced immunity. The region of HBsAg where most of these mutations occur is known as the major hydrophilic region (MHR). The aim of this study was to determine the prevalence and mutational patterns of MHR mutations in patients with chronic hepatitis B, and their correlation with patient characteristics, viral factors and antiviral therapy. The study comprised 164 plasma samples from patients with chronic hepatitis B, of which, 34.8% were on long-term lamivudine monotherapy. Direct sequencing of part of the S/pol gene was used for identification of HBsAg mutations, HBV genotypes, subgenotypes and HBsAg subtypes. The overall frequency of MHR mutations was 22.6%, but it varied significantly between untreated and treated patients (16.8% vs. 33.3%). The most frequent substitution was at position 120 (9.1%) whereas the most common vaccine-escape position, 145, was affected in 1.8% of isolates. The presence of MHR mutations was correlated with genotype D, subgenotype D3, and ayw2/ayw3 HBsAg subtypes and to older age (>40 years). It is concluded that natural viral variability present in a geographical region, duration of infection, and antiviral therapy are among the major factors associated with the occurrence of MHR mutations.

Epidemiological characteristics and clinical manifestations of acute non-A-E hepatitis.

BACKGROUND/AIM: Acute non-A, non-B, non-C, non-D, non-E hepatitis (non-A-E AH) is an acute disease of the liver of unknown etiology for which one or more new, so far undetected, hepatotropic viruses may be responsible. The frequency of non-A-E AH ranges from 3.8% to 33.9%, and therefore it has a significant place within current infectology and hepatology. The aim of our study was to establish the frequency, clinical and biochemical characteristics, natural course and outcome of non-A-E AH and compare them with control groups affected by acute viral hepatitis A, B and C. METHODS: This descriptive-analytic prospective study included 31 patients with non-A-E AH treated at the Institute of Infectious and Tropical Diseases, Clinical Center of Serbia, Belgrade, from 2003 to 2008. They were followed up during the period not less than 6 months. The controls involved randomly selected patients, treated at the same time with a definite diagnosis of acute viral hepatitis A, B and C. Statistical data analysis used Mann-Whitney U-test, Student's t-test and variance analysis. The value of p < 0.05 was considered statistically significant. RESULTS: The frequency of non-A-E AH was 7.6%. Almost no difference was found between sexes (male/female ratio was 1:1.07); it was developed in all age groups, with the highest incidence in the middle age (mean age was 38.32 +/- 15.3 years). It appeared equally throughout the whole year. Out of risk factors, inoculation risk was predominant (before all, dental interventions), mostly involving urban population living in comfortable conditions. The duration of incubation varied much ranging from 20 to 180 days (median 60 days). By clinical course, moderate and icteric forms were most common, mostly corresponding to acute hepatitis A and C. On the other hand, by duration of the disease (mean duration was 67.1 +/- 27.1) and chronic transformation, non-A-E AH resembled to acute hepatitis B. Progression to chronicity was recorded in 9.68% of the patients. There was no fulminant neither cholestatic form of the disease. CONCLUSION: Based on the results obtained in this study, it is probable that there are some so far undetected primary hepatotropic viruses in our environment.

Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).

AIMS AND BACKGROUND: The objective of this case-control study was to test the existing hypotheses about factors related to the occurrence of hepatocellular carcinoma in the population of Belgrade (Serbia). METHODS AND STUDY DESIGN: The investigation was conducted between 2004 and 2007 and consisted of 45 newly diagnosed, histologically confirmed hepatocellular carcinoma patients and 90 individually gender- and age-matched hospital controls. Conditional univariate and multivariate logistic regression analyses were applied. RESULTS: A highly statistically significant association (P = 0.001) was demonstrated between hepatocellular carcinoma and HBsAg positivity and the presence of hepatitis C virus antibodies. Diabetes mellitus was significantly (P = 0.018) associated with an increased risk of hepatocellular carcinoma. A statistically significant inverse association was shown between low parity and the risk of hepatocellular carcinoma (P = 0.033). The risk increased significantly with a longer history of cigarette smoking (P = 0.044), as well as the daily consumption of hard liquor (P = 0.049). A weekly intake of fish (P = 0.003) and yogurt (P = 0.003) and daily intake of boiled vegetables (P = 0.001) were reported more frequently by controls than hepatocellular carcinoma cases. In the current study, a high intake of salty food also significantly increased the risk of hepatocellular carcinoma (P = 0.027). Based on multivariate analysis, the presence of hepatitis C virus antibodies (OR = 24.6, P = 0.001) and duration of smoking > or =25 years (OR = 3.8, P = 0.020) were significantly related to hepatocellular carcinoma, whereas the daily consumption of boiled vegetables (OR = 0.1, P = 0.011) was inversely associated with the risk of hepatocellular carcinoma. CONCLUSIONS: The findings obtained in the current study support the hypotheses that non-viral factors, such as lifestyle factors, reproductive factors, and a history of diabetes, might be involved in the etiology of hepatocellular carcinoma.