Związek genotypu wirusa typu C zapalenia wątroby z przebiegiem wirusowego zapalenia wątroby oraz skutecznością jego leczenia u dzieci i młodzieŝy.

Transkrypt

1 Związek genotypu wirusa typu C zapalenia wątroby z przebiegiem wirusowego zapalenia wątroby oraz skutecznością jego leczenia u dzieci i młodzieŝy. Relation between genotype of hepatitis C virus with the course of hepatitis in children and teenagers and treatment efficiency. Ewa Łoś-Rycharska, Anna Szaflarska-Popławska, Anna Gronkowska, Teresa Woźniakowska-Gęsicka, Joanna Kupś, Magdalena Figlerowicz, Anna Liberek, Joanna Pawłowska, Mieczysława Czerwionka-Szaflarska Streszczenie WSTĘP: ZakaŜenie wirusem typu C zapalenia wątroby (HCV) jest powszechnym problemem. Wyodrębniono 6 genotypów wirusa z kilkudziesięcioma podtypami. W Polsce przewaŝa genotyp 1b, a u dzieci wg róŝnych źródeł 1a lub 1b. Rodzaj genotypu jest związany z przebiegiem zakaŝenia i skutecznością leczenia. CEL: Ocena związku genotypu wirusa typu C zapalenia wątroby z przebiegiem wirusowego zapalenia wątroby oraz skutecznością jego leczenia u dzieci i młodzieŝy. MATERIAŁ I METODY: 54 pacjentów, dzieci i młodzieŝy, z przewlekłym wirusowym zapaleniem wątroby typu C, w tym 9 nie kwalifikowanych do leczenia przeciwwirusowego i 45 po leczeniu, u których oznaczono genotyp wirusa typu C zapalenia wątroby, HCV-RNA oraz aktywność transaminazy alaninowej (AlAT). Przeprowadzono analizę retrospektywną dokumentacji medycznej. Porównano częstość występowania genotypów 1 i pozostałych pomiędzy pacjentami nie leczonymi oraz pacjentami leczonymi z róŝnym typem odpowiedzi wirusologicznej i biochemicznej na leczenie. WYNIKI: Genotyp 1 stwierdzano rzadziej u pacjentów z trwałą odpowiedzią wirusologiczną na leczenie (róŝnica bliska istotnej statystycznie p=0,09). Ponadto genotyp 1 wirusa występował statystycznie istotnie częściej u pacjentów, u których stwierdzano podwyŝszoną aktywność AlAT a rzadziej u pacjentów z prawidłowa aktywnością tego enzymu (p=0,02). Tylko w grupie pacjentów leczonych stwierdzono, Ŝe genotyp 1 częściej występuje wśród pacjentów, którzy mają po minimum 6 miesiącach od zakończenia leczenia zwiększoną aktywność AlAT (róŝnica na granicy istotności statystycznej, p=0,052). U pacjentów z aktualną wiremią HCV stwierdzono, Ŝe częściej genotyp 1 występuje u pacjentów z wysoką aktywnością AlAT w porównaniu z pacjentami z aktywnością prawidłową róŝnica była na

2 granicy istotności statystycznej (p=0,06). WNIOSKI: 1. Genotyp 1 występuje rzadziej u pacjentów z trwała odpowiedzią wirusologiczną na leczenie w porównaniu do pozostałych. 2. ZakaŜenie genotypem 1 HCV jest częściej niŝ zakaŝenie innymi genotypami wirusa związane z podwyŝszoną aktywnością AlAT. Słowa kluczowe: HCV, dzieci i młodzieŝ, leczenie Abstract BACKGROUND: Infection with hepatitis C virus (HCV) is a common problem. 6 virus genotypes with several dozen subtypes were distinguished. 1b subtype predominates in Poland, but according to various sources 1a or 1b types predominate in children. Genotype type is connected with infection course and treatment efficiency. PURPOSE: The aim of the study was to assess relation between genotype of hepatitis C virus with the course of hepatitis and its treatment efficiency in children and teenagers. MATERIAL AND METHODS: 54 patients, children and teenagers with chronic viral hepatitis C, including 9 who were not qualified for antiviral therapy and 45 patients after treatment, in whom genotype of hepatitis C, HCV-RNA and activity of alanine transaminase (AlAT) were assessed. Retrospective analysis of medical documentation was performed. Incidence of genotype 1 and other genotypes were compared in patients who were treated and were not treated and they also presented different type of virological and biochemical response to treatment. RESULTS: Genotype 1 was found more rarely in patients with persistent virological response to treatment (difference close to statistically significant p=0,09). Moreover genotype 1 of virus was observed statistically significantly more often in patients, in whom increased AlAT activity was noted, but more rarely in patient with normal activity of this enzyme (p=0,02). Concerning only the group of treated patients, genotype 1 occurs more often in patients who have increased AlAT activity after minimum 6 months after treatment ending (difference on the limit of statistical significance, p=0,052). Concerning patients with actual HCV viremia, genotype 1 occurs more often in patients with high AlAT activity in comparison with patients with normal activity (difference on the limit of statistical significance, p=0,06).

3 CONCLUSIONS: 1. Genotype 1 occurs more rarely in patients with persistent virological response to treatment. 2. Infection with HCV genotype 1 is connected with increased AlAT activity in comparison with infection with other types of virus. Key words: genotypes, HCV, children and teenagers, treatment

4 BACKGROUND, AIM HCV infection is a common problem it is estimated that about 3% of world population is infected with this virus, not excluding children [1]. It is estimated that as many as 2% of population is infected in Poland [2, 3, 4]. So high incidence of infections results from the facts that it was not possible to prepare efficient antiviral vaccine up to this time, due to considerable variability and genetic diversity of HCV and also because infection is often asymptomatic that favours its spread [5]. Children are usually asymptomatic HCV carriers, but the only specific symptom can be fatigue [6]. During last years it was possible to obtain decrease of incidence of new infections due to increased awareness of medical staff concerning blood-derived infections and also because of better and better procedures of infection prevention [7, 8]. During last years a team from our Department performed studies concerning epidemiology of HCV infections in infants, finding low incidence of this infection - 0,36 % [9]. Considering structure differences of various virus types, 6 virus genotypes with several dozen of subtypes were distinguished. Virus occurs in great number of varieties as a result of ease mutation, but also can produce a number of pseudotypes coexisting in the patients after infection. This fact causes worse circumstances for defence against it by host s immunological forces [5]. Genotype 1b predominates in Poland [10], but according to different sources, 1a [10,11,12] or 1b [13] predominates in children. According to Italian authors, scope of genotypes in children changes during last years: number of infections with genotypes 3 and 4 increases, but with genotype 1b decreases [8, 14]. On the base of studies concerning inflammatory reactions, Woźniakowska-Gęsicka et al. as early as in the nineties established clear relation of HCV infection course with virus genotype [15]. Italian authors prove that infection with genotype 3 in children can be connected with more frequent than in case of other genotypes, but particularly genotype 1, spontaneous viremia elimination during first years of child s life [14]. Moreover it was noted that manner of virus transmission can be connected with its genotype [12, 14]. Standard to diagnose infection is to detect genetic material of virus in the patient s serum, it means HCV-RNA. However single measurement of negative result can not be the base to exclude infection, because viremia can be changeable in chronic infection [1,5].

5 Interferon α has been applied for years to treat viral hepatitis. It is long-term therapy and also can have side effects [16], but its effectiveness is not satisfactory. Combined therapy with interferon α and ribavirin has recently been used also in children [17], that improved treatment efficacy [18, 19, 20, 21]. Also combined therapy with pegylated interferon and ribavirin is currently applied and this therapy is regarded as more effective, but considering children, it is still tested in phase of clinical analyses [22, 23, 24, 25, 26]. Virus elimination is still not obtained in considerable percentage of infected patients. It was proved that genotype type is strongly connected with treatment efficacy of interferon α and interferon α in combination with ribavirin, also in children [6, 20]. The aim of presented analyses was assessment concerning relation between genotype of hepatitis C virus with the course of viral hepatitis and its treatment effectiveness in children and teenagers. MATERIAL AND METHODS Together 54 patients were included into the study, children and teenagers till 18 years of age (average age 13,9 years) with chronic viral C hepatitis, including 31 boys and 23 girls. Analysed patients were treated in. The Chair and Department of Paediatrics, Allergology and Gastrorenterology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus Medical University in Toruń 22 patients, III Department of Paediatrics, Polish Mother s Memorial Hospital Research Institute in Łódź 17 patients, Department of Infectious Disease and Children Neurology III Department of Paediatrics Medical Faculty, Karol Marcinkowski Medical University in Poznań 12 patients, Department of Paediatrics, Gastroenterology and Oncology Medical Academy in Gdańsk 2 patients and Department of Gastroenterology, Hepatology and Immunology, The Children s Memorial Health Institute in Warsaw 1 patient. Patients were also treated in adequate outpatient clinic in above mentioned medical centres. 9 patients were not treated (NT no treatment), but remaining 45 patients were treated and finished treatment with interferon α (5 patients) or with interferon and ribavirin (40 patients) before minimum 6 months (during the years ). On average 2,8 years has passed since treatment was finished. At least 2 years have passed since therapy was finished in 27 of treated patients. Previously treated patients were divided into subgroups: with persistent

6 virological response (sustained for at least the whole 6 months after treatment ending) SVR sustained virological response, with transient virological response (only during the treatment and immediately after the treatment) TVR transient virological response and patients who do not response at all to treatment NR no response. Then also for the aims of this study, we used division into patients who eliminated hepatitis C virus after treatment at the time of the study and patients, in whom viremia still persists. Genotype of hepatitis C virus was determined in all patients, HCV-RNA with the use of PCR method (polymerase chain reaction) qualitative test and AlAT (normal range up to 40 U/l) were assessed. Moreover retrospective analysis of medical history concerning previous treatment of chronic viral hepatitis C was conducted, but particularly considering results of HCV-RNA and AlAT directly after treatment ending. These analyses were performed during the years Regarding only few patients infected with genotype other than 1 HCV, it was found that it is impossible to conclude about feature of genotype 3 or 4 HCV infection on the basis of own results. This fact and need to emphasize clinical characteristic of genotype 1 HCV infection in statistical analysis caused that we decided to connect groups of patients infected with HCV genotype 3 and 4. Incidence of genotype 1 and other remaining genotypes were compared among selected groups: not treated patients and treated patients with various type of virological and biochemical response to treatment. Mean AlAT activity was also compared between groups of patients infected with HCV genotype 1 and other genotypes. Statistical analysis of qualitative data was performed using chi 2 test of the highest reliability or with chi 2 test with Yates correction considering small number of patients with genotype different than 1. Quantitative data (comparison of mean values) were analysed with the use of t-student test or U Mann- Whitney s test after previous check of tests assumptions (distributions normality - Kołmogorov-Smirnov s test with Lilliefors correction, variance homogeneity Levene s test). Differences with p<0,05 were acknowledged as statistically significant. RESULTS It was established that the greatest number of patients were infected with genotype 1.

7 Precise distribution of obtained results was shown in table 1. Considering not great number of patients, in whom some of above mentioned results were obtained, for the aims of this study analysed group was divided into patients with genotype 1 (the highest number) and with 3 and 4 genotype (together only 9 patients). Considering comparable distribution of genotypes in particular sexes (shown in table 2), further analysis does not contain division into groups differing in sex. Genotype 1 was most often noted in all groups, but a bit more rarely in patients with persistent virological response to treatment. Comparing patients on account of present state (patients with persistent virological response, viremic patients after treatment and viremic patients who have not been qualified for treatment so far), it was also stated that there are no statistically significant differences among them on account of genotypes distribution. Results of this analysis were shown in table 3. Dividing all studied patients regarding AlAT activity, at the moment of performing this analysis it was stated that genotype 1 of the virus occurs statistically significantly more often in patients with increased AlAT activity, but rarely in patients with normal activity of this enzyme. Difference was statistically significant. Moreover, mean AlAT activity was statistically significantly higher in the group of patients with genotype 1. Results of this analysis were shown in table 4 and 5. Analysing only group of treated patients, there were no connection between incidence of particular HCV genotypes and type of virological response. Also analysing early virological response, statistically significant differences were not found. Statistically significant difference concerning incidence of particular genotypes among treated patients, who finally eliminated and not eliminated virus, was not noted as well. Tendency was only emphasized that it is more frequent incidence of genotype 1 in persisting viremic patients (without or with transient virological response). Results of this analysis were shown in table 6. Analysing biochemical response directly after treatment, there were no differences concerning genotypes distribution between patients with normal and increased AlAT activity. There was also no statistically significant difference between mean AlAT activity value in patients with genotype 1 and other genotypes, but there was marked tendency to higher AlAT activity in patients infected with genotype 1 of the virus. Analysis of AlAT activity at the moment of performing the study (biochemical response after minimum 6 months after

8 treatment ending) reveals that genotype 1 more often occurs in patients who have increased AlAT activity (difference on the limit of statistical significance). Moreover patients infected with HCV genotype 1 presented statistically significantly higher mean AlAT activity than in others. Results of this analysis were shown in table 5 and 7. Considering only patients, in whom at least 2 years have passed since treatment ending, we noted that genotype 1 and the others occur in similar frequency in patients who do not response to treatment regarding virusology and in patients with persistent and transient response. There was also no relation concerning virus genotype and virological response directly after treatment in this group of patients. There is also no statistically significant difference between patients treated at least 2 years before, who at present are viremic and are not viremic. Results of this analysis are shown in table 8. The relation of virus genotype to biochemical response directly after treatment was also not found in this group of patients. Late biochemical response (AlAT after minimum 2 years from treatment ending) was also not statistically significantly connected with HCV virus genotype. There was no statistically significant difference regarding mean AlAT activity at the moment of analysis concerning patients with genotype 1 in comparison with the others, but patients with genotype 1 presented statistically not significantly higher activity. These results are shown in table 5 and 9. Analysing only group of patients with actually detected HCV viremia, it was noted that there is no statistically significant difference concerning genotypes distribution between not treated or ineffectively treated patients both without response and only with transient virological response. However there was not statistically significant tendency that genotype 1 occurs more rarely in patients who were treated ineffectively from the beginning in comparison with not treated and patients with transient virological response. Comparing not treated patients and all patients treated ineffectively, there were also no statistically significant differences concerning genotypes distribution. Results of this analysis were shown in table 10. Comparing incidence of particular genotypes depending on AlAT activity in patients actually infected, it was stated that genotype 1 more often occurs in patients with high AlAT activity comparing with patients with normal activity difference was on the limit of statistical significance. Mean AlAT activity was statistically significantly higher in patients infected with HCV genotype 1. Results of this analysis were shown in table 5 and 11.

9 DISCUSSION It was proved on the base of this study that the greatest number of patients was infected with genotype 1, but particularly 1a. Tyczyno analysed adult patients and children and established that 1 genotype is predominant occurs in 71,3% of all patients, but this percentage is distinctly greater in adults 81% than in children 65% [27]. Also multi-centre Polish studies published in 2000 state that genotype 1 predominates in Poland, but there is distinct predominance of genotype 1b in adults (73%), but children more frequently than adults present genotype 1a [10]. Woźniakowska-Gęsicka et al. established that infection with genotype 1a most often occurs in Poland, but subsequently 1b [together 95% infected patients], rarely 3a [12]. Our studies report that incidence of genotypes other than 1 is actually 16,33%, and it is greater percentage than in cited above Polish authors [10, 12]. However Brojer et al. on the basis of their analysis established that the incidence if genotype 3 and 4 HCV has increased in recent years [28]. Tyczyno confirmed virus infections on the level of 14,7% with genotype 3 and 13,6% with genotype 4. This author also established that the incidence of HCV genotype 4 is especially high in pediatric patients and reaches 32% [27]. Italian researchers Bortolotti et al. [8] performed epidemiologic analysis of HCV infections in children within the space of several years. They stated that genotypes profile in children has changed since the nineties of last millennium: number of infections with genotypes 3 and 4 has increased, but with genotype 1b has decreased. They established that incidence of infection with genotypes other than 1 is actually over 30% [14]. Changes of incidence of particular genotypes especially concern children who were born after the year Probably such trend of changes results from presumed dependence of genotype 1 and the most frequent manner of virus transmission Italian authors state that nowadays mother-to child transmission way is the most frequent way of infections. Woźniakowska-Gęsicka et al. established that genotype 1a is very often connected with positive past history concerning past surgical operations or transfusions of blood and blood-derived preparations [12]. Our studies showed that genotype 1 more rarely occurs in patients with persistent virological response to treatment in comparison with all remaining groups, considering also patients who have not been qualified for treatment till now, it means patients whose infection

10 course did not fulfill criteria to include patient in therapy, for example increased aminotransferases activity (it was therefore relatively mild). This observation can confirm beneficial relation of infection with genotype other than 1 and treatment efficacy, described by many authors. On the other hand, relation concerning HCV infection course with particular virus genotype is not confirmed. It was surprising that we analysed only group of patients treated and we did not state statistically significant dependence concerning incidence of particular HCV genotypes and kind of virological response, but only tendency to more often incidence of genotype 1 in viremic patients, it means who do not response to treatment or with transient response. Whereas correlation concerning genotype type with distant [at least after 6 months] biochemical response to treatment revealed to be more distinct and genotype 1 was connected with increased AlAT activity. Genotype 1 is described as bad prognostic sign for treatment of chronic viral hepatitis C both in monotherapy and in combined therapy. Iorio et al. [6] and Bortolotti et al. [8, 14] report that persistent virological response to treatment with interferon α is connected with infection with genotype different than 1. American authors stated higher percentage of persistent viremia elimination in patients infected with genotypes 2 and 3 in comparison with infected with genotype 1, after combined therapy [21]. Results of multicentre studies concerning efficacy of treatment with pegylated interferon and rybavirin indicate high enough frequency of viremia elimination that reaches over 55%, but it is over 80% in infections with genotypes other than 1, but only slightly over 50% in infection with genotype 1 [20]. It was established on the base of our results that infection with genotype 1 is distinctly connected with increased AlAT activity, both among treated and not treated patients, but also in patients who were viremic at the moment of observation, independently on treatment. It suggests relation of genotype 1 with more stormy infection course and with potentially major liver damage during infection course. Meanwhile after all, concerning patients with actual HCV viremia, we stated that there is no statistically significant difference of genotypes distribution among patients not treated or treated ineffectively, it means in whom previous infection course was milder and between those, in whom hypertransaminasemia was observed as one of qualification criterion for treatment. Increase of aminotransferases activity that is not common and persistent event during the course of hepatitis C infection and can prove disadvantageous inflammatory processes in

11 the liver that results in its damage, but can also be an advantageous prognostic factor for example of spontaneous virus elimination. Concerning our observations, hypertransaminasemia was more often connected with infection with genotype 1 and that is why it can be supposed that hypertransaminasemia did not be a sign of neither spontaneous viremia elimination nor recovery that are not connected with this genotype type [14, 15]. CONCLUISIONS 1. The relation of HCV genotypes with efficiency of antiviral treatment exists - genotype 1 occurs more rarely in patients with persistent virological response to treatment. 2. The relation of HCV genotypes with course of HCV infection exists occurrence of genotype 1 is connected with increased AlAT activity. REFERENCES 1. Juszczyk J. Hepatitis C. Vademecum diagnostyki i leczenia przeciwwirusowego. Poznań: Termedia; 2003, 32p. 2. Halota W, Pawłowska M. Diagnozowanie i leczenie zakaŝeń HCV. Stand Med. 2004; 1: Braczkowska B, Kowalska M, Zejda J, Beniowski M, Kulawik I, Kuleszyński J, Jagodziński L. Prevalence and basic determinants of hepatitis C antibodies in medical students in Katowice, Poland. Prz Lek 2006; 63: Szaflarska-Popławska A, Murawska S, Czarnecki R, Kuczyńska.R. Częstość zakaŝeń HCV u dzieci i młodzieŝy. Pediatr Pol. 2005; 80: Juszczyk J. Wirusowe zapalenia wątroby. Warszawa: PZWL; 352 p. 6. Iorio R, Giannattasio A, Sepe A, Terracciano LM, Vecchione R, Vegnente A. Chronic hepatitis C in childhood: an 18-year experience. Clin Infect Dis. 2005; 41: Chlabicz S, Sawicka-Powierza J, Kovalchuk O, Kłoczko J, Radziwon P, Wojtukiewicz M. Częstość występowania zakaŝeń wirusem zapalenia wątroby typu C (HCV) u osób ze schorzeniami hematologicznymi i onkologicznymi leczonych preparatami krwiopochodnymi. Prz Lek. 2005; 62: Bortolotti F, Iorio R, Resti M, Cammà C, Marcellini M, Giacchino R et al. Italian Observatory for HCV Infection and Hepatitis C in Children. Epidemiological profile of

12 806 Italian children with hepatitis C virus infection over a 15-year period. J Hepatol. 2007; 46: Swincow G, Nowak A, Czarnecki R, Czerwionka-Szaflarska M. Częstość zakaŝenia HCV u niemowląt w świetle własnych obserwacji. Med Wieku Rozw 2006; 10: Brojer E, Grabarczyk P, Medyńska J, Moraczewska Z, Kołtan S, DzierŜanowska K et al. Analiza częstości występowania genotypów wirusa HCV u chorych na zapalenie wątroby oraz u bezobjawowych nosicieli wirusa w róŝnych regionach kraju - badania wieloośrodkowe. Hepatol Pol 2000; 7: Januszkiewicz-Lewandowska D, Wysocki J, Rembowska J, Pernak M, Lewandowski K, Nowak T et al. Transmission of HCV infection among long-term hospitalized oncohaematological patients. J Hosp Infect. 2003; 53: Woźniakowska-Gęsicka T, Zeman K, Kupś J, Dworniak D, Płaneta-Małecka I. Analiza częstości występowania HCV-RNA i genotypów wirusa C (HCV) u dzieci chorych na przewlekłe zapalenie wątroby. Hepatol Pol 1997; 4: Czerwionka-Szaflarska M, Chrobot A, Szaflarska-Szczepanik A. Studies of the effectiveness of interferon alpha treatment for chronic hepatitis C in children. Med Sci Monit 2000; 6: Bortolotti F, Resti M, Marcellini M, Giacchino R, Verucchi G, Nebbia G et al. Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: changing distribution and correlation with clinical features and outcome. Gut 2005; 54: Woźniakowska-Gęsicka T, Zeman K, Wiśniewska-Ligier M, Kupś J, Puchała B, Głowacka E et al. Serum levels of IL-1á, IL-6, TNF-ŕ and stnfrp55 in children with chronic hepatitis C in respect to HCV genotype. Int Rev Allergol Clin Immunol. 1998; 4: Szaflarska-Szczepanik A, Łoś E, Chrobot A, Michalska K, Czerwionka-Szaflarska M. Adverse reactions to interferon alpha treatment in children with viral hepatitis. Med Sci Monitor 1999; 5: SłuŜewski W, Cianciara J. Zalecenia Sekcji Pediatrycznej Polskiego Towarzystwa Epidemiologów i Lekarzy Chorób Zakaźnych dotyczące standardów leczenia wirusowego zapalenia wątroby typu B i C u dzieci Zakopane r. Med Sci Monitor 2004; 10 (suppl 4): 2-3.

13 18. Kacprzak-Bergman I, Zaleska I, Gruszka J, Jasonek J, Czerniak T, Szenborn L et al. Ocena skojarzonego leczenia interferonem alfa i rybawiryną dzieci z przewlekłym zapaleniem wątroby typu C. Pediatr Pol. 2006; 81: Woźniakowska-Gęsicka T, Kupś J, Wiśniewska-Ligier M. Trwała odpowiedź wirusologiczna u dzieci z przewlekłym zapaleniem wątroby typu C leczonych interferonem alfa i rybawiryną. Prz Lek. 2005; 62: Juszczyk J, Baka-Ćwierz B, Beniowski M, Berak H, Bolewska B, Boroń-Kaczmarska A et al. Pegylowany interferon ŕ-2a z rybawiryną w leczeniu przewlekłego wirusowego zapalenia wątroby typu C (raport końcowy z badań). Prz Epidemiol 2005; 59: González-Peralta RP, Kelly DA, Haber B, Molleston J, Murray KF, Jonas MM et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005; 42: Simon K, Gładysz A, Rotter K, Rymer W, Smoliński P, Inglot M et al. Cost effectiveness of replacing recombinated interferon ŕ-2b with its pegylated form in combination with ribavirin for the therapy of chronic HCV infection in Poland. Adv Clin Exp Med. 2006; 15: Kowala-Piaskowska A, Figlerowicz M, Mozer-Lisewska I, SłuŜewski W. Wyniki leczenia dzieci z przewlekłym zapaleniem wątroby typu C pegylowanym interferonem i rybawiryną. Prz Epidemiol 2005; 59: Kowala-Piaskowska A, Słuzewski W, Figlerowicz M, Mozer-Lisewska I. Early virological response in children with chronic hepatitis C treated with pegylated interferon and ribavirin. Infection 2007; 35: Jara P, Hierro L, de la Vega A, Díaz C, Camarena C, Frauca E et al. Efficacy and safety of peginterferon-alpha2b and ribavirin combination therapy in children with chronic hepatitis C infection. Pediatr Infect Dis J. 2008; 27: Kowala-Piaskowska A, Słuzewski W, Figlerowicz M, Mozer-Lisewska I. Factors influencing early virological response in children with chronic hepatitis C treated with pegylated interferon and ribavirin. Hepatol Res 2005; 32: Tyczyno M. Genotypy HCV wśród pacjentów diagnozowanych w Bydgoszczy. Med. Sci. Rev. Hepatol. 2007; 7: 77-9

14 28. Brojer E, Grabarczyk P, Kopacz A, Potępa A, Medyńska J, Smolarczyk-Wodzyńska J et al. Genotypy HCV u polskich dawców krwi w okresie Prz Epidemiol 2008; 62: