Hepatitis C virus (HCV) genotype 1 NS5A resistance-associated variants are associated with advanced liver fibrosis independently of HCV-transmission clusters.

OBJECTIVES: The aim of the study was to characterize the differences in the frequencies of NS3 and NS5A resistance-associated variants (RAVs) among Polish therapy-naive genotype 1 (G1) hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients including clustering patterns and association of RAV frequency with liver fibrosis. METHODS: NS3/NS5A RAVs were identified by population sequencing in 387 directly acting antiviral treatment-naive G1-infected individuals (54 with genotype 1a (G1a) and 333 with genotype 1b (G1b)). Liver fibrosis was assessed based on histopathology or ultrasound elastography. Phylogenetic clusters were identified using maximum likelihood models. For statistics, chi-squared or two-sided Fisher's exact tests and multivariate logistic regression models were used, as appropriate. RESULTS: NS3 RAVs were found in 33.33% (18/54) for G1a and 2.62% (8/297) for G1b whereas NS5A variants were present in 5.55% (3/54) G1a and 9.31% (31/333) G1b sequences. Variations in NS5A 31 and 93 codon positions were found only in G1b (4.2% (14/333) for L31I/F/M and 5.39% (17/333) for Y93H). NS5A RAVs were more frequent among patients with advanced liver fibrosis (17.17% (17/99) for F3-F4 versus 6.94% (17/245) for F0-F2; p 0.004) or liver cirrhosis (20.34% (12/59) for F4 versus 7.72% (22/285) for F0-F3; p 0.003). Liver cirrhosis (F4) was associated with higher odds ratio of the NS5A RAVs among HCV-infected patients (odds ratio 2.34, 95% CI 1.004-5.291; p 0.049). NS5A RAVs were less frequent among sequences forming clusters and pairs (5.16% (8/155) versus 11.21% (26/232); p 0.039). CONCLUSIONS: Presence of NS5A RAVs correlated with progression of liver fibrosis and represents de novo selection of variants rather than transmission of drug resistance. Hence, the presence of NS5A RAVs may be a predictor for a long-lasting HCV infection.

Treatment of HCV infection in Poland at the beginning of the interferon-free era-the EpiTer-2 study.

The aim of the EpiTer-2 study was to analyse patient characteristics and their medication for HCV infection in Poland at the beginning of the interferon-free era. Analysis of data of HCV infected patients treated during the initial period of availability of interferon-free regimens in Poland, who started therapy after 1 July 2015 and had available an efficacy evaluation report before 30 June 2017 was undertaken. A total of 2879 patients with chronic hepatitis C were entered, including 46% with liver cirrhosis. The most common was genotype 1b (86.8%). The study population was gender balanced, the majority of patients were overweight or obese and 69% presented comorbidities, with the highest prevalence that for hypertension. More than half of patients were retreated due to failure of previous therapy with pegylated interferon and ribavirin. Almost two-third of patients received current therapy with ombitasvir/paritaprevir/ritonavir±dasabuvir (OPrD) ±ribavirin. Other patients received mostly sofosbuvir-based regimens including combination with ledipasvir and pegylated interferon and ribavirin for genotype 3-infected patients. Efficacy of treatment in the whole study population measured as intent-to-treat analysis was 95%. The most frequent regimen, administered for patients infected with genotype 1b, was 12 weeks of OPrD, resulting in an SVR rate of 98%. At least one adverse event was reported in 38% of patients, and the death rate was 0.8%. In conclusion, data from the EpiTer-2 study confirmed the excellent efficacy and safety profile of the real-world experience with recently introduced therapeutic options for genotype 1 HCV infection, but demonstrated weakness of the current therapeutic programme regarding genotype 3 infections.

Real-world effectiveness and safety of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C: AMBER study.

BACKGROUND: Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre-registration studies. AIM: To confirm these clinical trial findings in the treatment of genotype 1 and 4 hepatitis C under real-world conditions. METHODS: Patients enrolled for treatment with OBV/PTV/r ± DSV ± RBV based on therapeutic guidelines were included, and the regimen was administered according to product characteristics. Clinical and laboratory data, including virologic response, were collected at baseline, end of treatment (EOT) and 12 weeks after EOT. RESULTS: A total of 209 patients with chronic hepatitis C were enrolled, most were genotype 1b-infected (84.2%) and 119 (56.9%) had liver cirrhosis. Among these, 150 (71.7%) had failed previous anti-viral therapies and 84 (40.2%) were null-responders. At 12 weeks after EOT, SVR was achieved by 207 (99.0%) patients, ranging from 96.4% to 100.0% across subgroups. All Child-Pugh B and post-orthotopic liver transplantation patients achieved SVR. Adverse events occurred in 151 (72.2%) patients and were mostly mild and associated with the use of RBV. Serious adverse events, including hepatic decompensation, renal insufficiency, anaemia, hepatotoxicity and diarrhoea, were reported in eight (3.8%) patients. In five (2.4%) patients, adverse events led to treatment discontinuation. On-treatment decompensation was experienced by seven (3.3%) patients. CONCLUSIONS: The results of our study confirm previous findings. They demonstrate excellent effectiveness and a good safety profile of OBV/PTV/r± DSV±RBV in HCV genotype 1-infected patients treated in the real-world setting.

Risk score based PEG Interferon alpha 2b and Ribavirin treatment response estimation model for genotype 1 chronic hepatitis C patients.

PURPOSE: Attempt to create simple practical algorithm for prospective assessment of PEG interferon/ribavirin related treatment response in individuals with chronic hepatitis C (CHC) basing on the risk factors defined prior to the treatment initiation. MATERIAL/METHODS: Retrospective assessment of 45 female and 39 male previously untreated CHC patients aged 20 to 73 years, with genotype 1, undergoing standard treatment with PEG-IFNa2b+RBV was performed. For the final analysis 78 patients were included (38 effectively treated and 40 treatment failures). Thirty-six sustained virological response (SVR) related factors, which were routinely measured before treatment initiation were compared (including physical, biochemical, serologic and histopathologic). From this group the risk factors of the highest predictive value for treatment failure were selected. Cut-off values for statistical significance were defined for each parameter, with risk score (RS) calculated and compared in the group with and without SVR. RESULTS: Seven factors related to treatment failure were identified: HCV>600000 IU/L, blood platelet count <150000/ul, GGTP>45 IU/ml, total serum protein<7.8 g/dl, glycaemia>105 mg/dl, detectable HBc IgG antibodies and cirrhosis. In the group with RS 1 the likelihood of SVR was 70% (p<0.028), while in patients with RS 3 the response was reduced to 23.8% (p<0.016), with no SVR achieved among patients with RS >3. CONCLUSIONS: Low risk score (0-2) is associated with high probability of treatment success with scores >3 predictive for treatment failure. The presented model is a simple tool for prediction of treatment success for clinical use before PegIFN/RBV treatment initiation among genotype 1 CHC patients.

Natural history of acute symptomatic hepatitis type C.

BACKGROUND: Spontaneous clearance of hepatitis C virus (HCV) after acute hepatitis C, and the course of chronic HCV infection in patients who did not clear the virus, were studied. PATIENTS AND METHODS: Patients with acute C or non-A, non-B hepatitis who were hospitalized between 1988 and 1998 were called for evaluation in 2001. They were tested for anti-HCV, serum HCV-RNA, HCV-RNA in peripheral blood mononuclear cells (PBMC) and liver enzymes. A liver biopsy was performed on chronically infected patients. The course of acute hepatitis C was compared between HCV-RNA-positive and negative subjects to look for factors that might influence spontaneous viral clearance. Factors influencing more progressive liver disease were analyzed in chronic hepatitis C. RESULTS: Out of 159 acute hepatitis C patients, 77 (48.4%) participated in the study, and the median observation time was 8 years. Spontaneous clearance of serum HCV was found in 23 subjects (29.9%), but in two cases HCV-RNA was detected in peripherical blood mononuclear cells (PBMC). Only three patients negative for HCV-RNA in serum and PBMC lost anti-HCV. Severity of acute HCV infection and previous alcohol abuse seemed to influence resolution. In non-alcoholic patients, older age at time of primary infection was a significant predictor of virus clearance. In chronic hepatitis C, more than 75% of patients had minimal or mild activity in biopsy, but 40% had advanced fibrosis. Older age at infection, male gender, alcohol abuse, and higher iron content were connected with advanced fibrosis. CONCLUSION: Studies on HCV infection resolution should include at least PBMC testing for HCV-RNA. A healthy carrier state of HCV can be discussed. A longer observation time increased the likelihood of seroreversion. Fibrosis in chronic hepatitis C probably is not a direct result of inflammatory activity.

Serum iron parameters in patients with alcoholic and chronic cirrhosis and hepatitis.

BACKGROUND: The aim of our study was to asses the serum iron status of patients with various forms of hepatitis and cirrhosis of the liver and to determine the correlation between the degree of hepatocyte damage and the status of serum iron parameters. MATERIAL AND METHODS: The study involved 136 subjects with chronic viral hepatitis type C (group I, n=71) and type B (group II, n=29), alcoholic cirrhosis of the liver (group III, n=15), postinflammatory cirrhosis of the liver (group IV, n=13), and alcoholic hepatitis (group V, n=8). In all these patients, serum alanine (ALT) and aspartate (AST) aminotransferase activity were used as a secondary measure of necroinflammatory activity. The serum iron status measurements included iron concentration (Fe), total iron-binding capacity (TIBC), transferrin saturation, and ferritin concentration. RESULTS: Our study results led us to conclude that the mean value of serum iron concentration did not differ significantly among the analysed groups (p>0.05). The transferrin value - estimated as the total iron-binding capacity (TIBC) - was significantly lower in alcoholic cirrhosis of the liver in comparison to both chronic hepatitis C (p<0.004) and chronic hepatitis B (p<0.04). The transferrin saturation was statistically the higher in group III in comparison with both group I (p<0.0031) and group II (p<0.024). Serum ferritin was significantly higher in cirrhotic patients regardless of etiology, in comparison with patients with chronic viral hepatitis (p<0.045). We found correlation between an increase of both AST and ALT and a higher level of ferritin in patients with chronic hepatitis type C (p<0.005, p<0.02) and type B (p<0.05, p<0.03) and alcoholic hepatitis (p<0.05). CONCLUSIONS: In the course of chronic liver diseases we may observe slight irregularities in iron status relating to both the serum and store pool of this element. The most significant disturbances are seen in patients with alcoholic cirrhosis of the liver.

[Effectiveness of antiviral treatment of patients with chronic hepatitis C (a Polish multicenter study)]. / Efektywnosc leczenia przeciwwirusowego przewleklego zapalenia watroby typu C (wieloosrodkowe badania pòlskie).

Interferon alpha (INF) is routine treatment in patients with chronic hepatitis C. Many controlled investigations were evaluated to establish the optimal schedule of treatment with sustained virological and biochemical response. Recently, multicentre meta-analyses suggest that combination therapy (INF + Ribavirin) was more effective than treatment with interferon alone. The aim of this study was to compare the efficacy of four schedules of antiviral treatment in 445 patients with chronic hepatitis C. Combination therapy (INF + Ribavirin) given for 6 mo. and monotherapy (INF) for 18 mo. were more effective than interferon alone given for 6 mo. Treatment with INF alone for 6 mo. was demonstrated to be insufficient.

Hospital-treated infectious diseases in Western Pomeranian region in a 5-year surveillance: importance for travellers.

Retrospective analysis of the incidence of infectious diseases in the five-year period 1994-1998 as recorded by the Department of Infectious Diseases of the Pomeranian Medical School, has been presented. In this period contagious diseases were diagnosed in 3,863 adults with mean age of 42.8 +/- 33.5 y. Most patients still had viral liver diseases, but we observe some major changes in the epidemiology of infectious diseases in our region. There is an increased number of hospitalisations due to chronic hepatitis and liver cirrhosis as well as due to symptomatic HIV infections, whereas some acute diseases namely acute hepatitis B and infectious intoxication show decreasing tendency.

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland.

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.

[A patient with abdominal actinomycosis--diagnostic problems]. / Chora z promienica brzuszna--problemy diagnostyczne.

The difficulties in diagnosis of abdominal actinomycosis are presented. Clinical manifestations and colonoscopy suggested malignancy. Final diagnosis was made on the basis of pathological assessment of resected sigmoid. Authors underline that in case of "negative" pathomorphological results of material obtained during endoscopy from lesions suspected, benign disease should be consider including anctinomycosis and intraoperative pathomorphological examination should be performed.

[A case of spontaneous elimination of HBsAg and seroconversion of HBe after infection with HCV virus]. / Przypadek spontanicznej eliminacji HBsAg oraz serokonwersji w ukladzie HBe po zakazeniu wirusem HCV.

A case of chronic type B hepatitis with HBsAg persisting for 15 years and its clearance as well as HBeAg-->HBeAb seroconversion and histological improvement after acute HCV superinfection is described. Possible mechanisms of suppressive effects of acute HCV superinfection on the established HBV infection is discussed.

[The course of acute HCV infection in patients with chronic non-A, non-B hepatitis]. / Przebieg ostrego zakazenia HCV u chorych na przewlekle zapalenie watroby NANB.

Among 52 patients with chronic non-A, non-B hepatitis, observed for many years in the Department of Infectious Diseases of Pomeranian Medical Academy, retrospectively diagnosed towards HCV infection, 45 proved to be anti-HCV positive. Sera stored in the bank of sera were examined using 2nd generation tests: ABBOTT HCV EIA (Abbott), ORTHO RIBA (Ortho Diagnostics) and UBI HCV EIA (Organon), showing 85% of positivity. Mostly HCV infection was connected with the blood transfusion. The course of acute phase of HCV infection was mild, short lasting, with no or sporadic extrahepatic symptoms; the activity of aminotransferases and the bilirubin level were of average value. The only characteristic feature of the acute HCV infection was fluctuating aminotransferase activity, which can be the good sign of progression.

[Viral hepatitis as a nosocomial infection in the western Pomeranian region in the years 1984-1990]. / Wirusowe zapalenie watroby jako zakazenie szpitalne na Pomorzu Zachodnim w latach 1984-1990.

Within last six years almost 25% hospitalized cases of viral hepatitis (1390 among 5748 patients) were diagnosed as nosocomial infections. Transfusion anamnesis was excluded in 80% patients with type B hepatitis and in 43% patients with NANB hepatitis. One case of nosocomial hepatitis for every 1000 hospitalized in this region was calculated.

[A case of Listeria meningoencephalitis with a fatal result]. / Przypadek listeriozowego zapalenia osrodkowego ukladu nerwowego zakonczony zejsciem smiertelnym.

A fatal case of severe meningoencephalitis caused by Listeria monocytogenes in a compromised alcoholic has been described. Unconsciousness, full meningeal symptoms with slight lateralisation of signs, seizures, respiratory failure within three days before death have been observed.