efficacy of treatment with pegylated interferon and ribavirin in patients ...

Download PDF
3 downloads 0 Views 471KB Size Report
Comment
Tsung-Ming Chen, Pi-Teh Huang,Ching-Heng Lin, Ming-Hung. Tsai, Lien-Fu Lin, Chung- Cheng Liu, et al. Feasibility of indi- vidualized treatment for hepatitis C ...
moksliniai tyrimai

EFFICACY OF TREATMENT WITH PEGYLATED INTERFERON AND RIBAVIRIN IN PATIENTS WITH CHRONIC HCV INFECTION “UNDER REAL LIFE“ CONDITIONS SERGANČIŲJŲ LĖTINIU VIRUSINIU C HEPATITU GYDYMO PEGILIUOTU INTERFERONU IR RIBAVIRINU EFEKTYVUMAS KLINIKINĖJE PRAKTIKOJE Danutė Speičienė1, Lina Kotovienė2, Artautas Mickevičius3, Valentina Liakina1,4, Jonas Valantinas1 Vilniaus universiteto Medicinos fakulteto Gastroenterologijos, nefrourologijos ir chirurgijos klinika VšĮ Centro poliklinika 3 Vilniaus universiteto ligoninės Santariškių klinikos 4 Vilniaus Gedimino technikos universiteto Biomechanikos katedra 1 2

Vilnius University, Medical Faculty, Clinic of Gastroenterology, Nephrourology and Surgery Public Institution Central Outpatient Clinic 3 Vilnius University Hospital Santariskiu Klinikos 4 Vilnius Gediminas Technical University, Department of Biomechanics 1 2

SANTRAUKA Reikšminiai žodžiai: virusinis C hepatitas, gydymas. Tikslas. Įvertinti sergančiųjų lėtiniu virusiniu C hepatitu antivirusinio gydymo pegiliuotu interferonu ir ribavirinu efektyvumą rutininės gydymo praktikos sąlygomis ir palyginti rezultatus su randomizuotų klinikinių tyrimų duomenimis. Ligoniai ir tyrimo metodai. Atliktas retrospektyvus tyrimas: nagrinėtos 203 ligonių (2003–2009 m.), kurie sirgo lėtiniu virusiniu C hepatitu, asmens sveikatos istorijos ir jose pateikti duomenys. Ligoniai buvo gydomi pegiliuoto interferono ir ribavirino deriniu, remiantis Lietuvoje patvirtinta metodika. Gydymo efektyvumas, t. y. stabilus virusinis atsakas (HCV RNR neaptinkamas po 24 sav. baigus gydymą), buvo vertintas 179 ligoniams. Rezultatai. Bendrai stabilus virusinis atsakas (SVA) buvo pasiektas 43 proc. ligonių (iš jų 51,3 proc. dar negydytų ir 28,1 proc. anksčiau nesėkmingai gydytų). Dar negydytų HCV genotipo 1 ligonių SVA buvo 38,8 proc., genotipo 2 – 100 proc., genotipo 3 − 82,6 proc., o nereagavusių į buvusį gydymą ligonių SVA – 17 proc. genotipo 1 ir 64,3 proc. genotipo 3 atvejų. Pastebėta statistiškai reikšminga SVA ir HCV genotipų koreliacija: 68,9 proc. genotipo 1 ligonių gydymas buvo nesėkmingas, o 80 proc. ir 75,7 proc. užkrėstųjų genotipu 2 ir 3 pasiekė SVA (atitinkamai p < 0,005 ir p = 0,01). Daugiavariantinė analizė patvirtino atvirkštinę SVA koreliaciją su amžiumi (p < 0,01), fibrozės laipsniu (p = 0,039) ir buvusiu nesėkmingu gydymu (p = 0,002). Išvados. Antivirusinio gydymo rezultatai „realaus gyvenimo“ sąlygomis, palyginti su randomizuotų klinikinių tyrimų duomenimis, nevienareikšmiai: negydytų ir anksčiau nesėkmingai gydytų ligonių užkrėstų 1 genotipo C virusu SVA duomenys buvo panašūs ar truputį mažesni nei klinikinių tyrimų, tuo tarpu genotipu 3 − kur kas geresni. Nesėkmingas ankstesnis gydymas, genotipas 1, vyresnis amžius, ženkli fibrozė ir cirozė yra blogo virusinio atsako pranašai.

ABSTRACT Key words: hepatitis C, antiviral treatment. Objective. To investigate the outcomes of combined therapy of hepatitis C (HCV) patients with peginterferon and ribavirin in ”real life” practice, to compare them with data obtained in randomized clinical trials (RCT) and to evaluate possible predictors of sustained virological response (SVR). Material and methods. The retrospective study of HCV patients routinely examined and treated in the Vilnius University Hospital Santariskiu Klinikos (2003−2009 yrs) was carried out. They had undergone the treatment with combination of peginterferon alfa and ribavirin according to the Lithuanian guide. Overall 203 patients were enrolled. SVR was evaluated in 179 patients. Results. The overall rate of SVR was 43 %: in 51,3 % of naives (genotype 1 − 38,8 %, genotype 2 – 100 %, genotype 3 − 82,6 % cases) and in 28,1 % of experienced patients (genotype 1 – 17 %, and genotype 3 – 64,3 % cases). Significant relations of Valentina Liakina VUL Santariškių klinikų Hepatologijos, gastroenterologijos ir dietologijos centras Santariškių g. 2, Vilnius [email protected] teorija ir praktika 2015 - T. 21 (Nr. 1), 23–32 p. doi:10.15591/mtp.2015.004

23

moksliniai tyrimai SVR and HCV genotype was observed: 68,9 % having genotype1 were non-responders, whereas 80 % and 75,7 % ones with genotype 2 and 3 achieved SVR (p < 0.005 and p = 0.01, respectively). The inverse relation with the age (p < 0.01), degree of fibrosis (p = 0.039) and previous unsuccessful treatment was confirmed by multivariate analysis. Conclusions. Data of SVR obtained „on real life“ conditions are non unambiguous: SVR of naive and experienced patients overall and those with genotype 1 were similar or slightly lower, while for patients with genotype 3 significantly higher than results presented in clinical trials. Genotype 1, previous unsuccessful antiviral treatment, older age, and advanced fibrosis were strongest negative predictors for SVR.

INTRODUCTION Chronic hepatitis C virus (HCV) infection has reached pandemic proportions, with an estimated 170 million individuals infected worldwide and approximately 70 000–80 000 in Lithuania, which represents an overall prevalence rate of about 2–2.8 % [1–3]. Although the course of the disease is highly variable, approximately 20–30 % of patients develop cirrhosis – end-stage liver disease, or hepatocellular carcinoma. Fortunately, treatment with current standard of care, peginterferon and ribavirin (double therapy) and implemented in 2011–2014 yrs new generation of direct acting antivirals (using together with peginterferon and/or ribavirin or without), can improve substantially the treatment results, reduce the complications of chronic liver disease and hopefully solve hepatitis C problem [4, 5, 6, 7, 8]. The 2002 NIH Consensus Development Conference and recent guidelines for double therapy including Lithuanian guidelines recommend that all patients with chronic hepatitis C (CHC) should be considered as potential candidates for this therapy [9–15]. These agents yield sustained virological response (SVR) rates of about 40–45 % in patients with genotype 1 and 75–80 % in patients with genotypes 2 and 3. However, these data of efficacy are obtained by randomized controlled trials performed on patients selected using strict inclusion and exclusion criteria, which means that those patients not necessarily represent the HCV population treated in routine clinical practice in terms of disease severity or presence of co-morbidities [16]. In the normal clinical setting a greater variety of patients are being treated. In addition treatment efficacy may also be influenced by the occurrence of adverse events, a problem that may be of great importance in developing countries or in geographical areas with high prevalence of CHC where the majority of patients are treated outside randomized controlled trials [17]. Imperfect patients adherence to combination therapy is common in routine clinical practice and possibly may also diminish effectiveness of the treatment [18]. Therefore the efficacy of antiviral treatment and predictors of treatment success in “real life” practice may differ from that in clinical trials and remain to be established. The reports on the „true life” results of pegylated interferon and ribavirin in treatment-naive patients are controversial. Re24

trospective, observational cohort study presented SVR rates lower, than in clinical trials, in 20 %, 52 % and 43 % in genotypes 1, 2 and 3, respectively [19]. At general population level effectiveness of antiviral treatment for hepatitis C in a highly endemic area was also found being lower than in clinical trials (SVR – 37.5 % vs more than 50 %). On the other hand there are converse data too: the treatment results of an unselected population of patients with CHC in a routine clinical practice was found comparable to that observed in controlled clinical trials[20]. Many factors are known to influence the SVR: HCV genotype, pretreatment viral load, age, BMI, γGT level, presence of cirrhosis or advanced fibrosis, insulin resistance and hepatic steatosis, cholesterol level, history of drug abuse and others [21]. The aim of this open non-randomized retrospective study was to investigate the treatment outcomes of combined therapy with peginterferon and ribavirin in treatment naive and treatment experienced HCV patients, to compare them with data of randomized clinical trials (RCT) and to evaluate possible predictors of SVR. No reports on chronic HCV infection treatment data with pegylated interferon and ribavirin “in real life“ conditions in Lithuania have been published yet. MATERIAL AND METHODS Study Population The retrospective observational study analyzing antiviral treatment response of HCV patients routinely examined and treated in the inpatient and outpatient departments of the Centre of Hepatology, gastroenterology and dietetics Vilnius University Hospital Santariskiu Klinikos in 2003–2009 years was carried out. The analysis of case records of the patients with chronic HCV infection who had undergone treatment with either peginterferon alfa-2a/ PegIFN2a (Pegasys, Roche) and ribavirin/RBV (Copegus, Roche) or peginterferon alfa-2b/PegIFN2b (PegIntron, Shering-Plough) and ribavirin/RBV (Rebetol, ScheringPlough) was made. Patients data collection was performed via Centre electronic database and patients record forms. Overall 203 patients – 107 (52,7 %) males and 96 (47,3 %) females (age 19–77 yrs) were enrolled into the study and stratified by presence or absence of previous treatment into teorija ir praktika 2015 - T. 21 (Nr. 1)

moksliniai tyrimai

two groups: naives – non-treated – 125 (61,6 %) and experienced – previously unsuccessfully treated – 78 (38,4 %) (Fig. 1). HCV antibodies were identified with a microparticle enzyme immunoassay (AxSYM hepatitis C virus version 3.0; Abbott Laboratories, 65205 Wiesbaden, Germany), and qualitative and quantitative HCV ribonucleic acid determinations were made by polymerase chain reaction (PCR) (AMPLICOR hepatitis C virus Test, version 2.0 and AMPLICOR hepatitis C virus Monitor Test, version 2.0, respectively; Roche Diagnostics GmbH, D-68298 Mannheim, Germany). HCV genotyping and subtyping were performed via PCR followed by a line probe assay (INNO-LiPA hepatitis C virus II; Innogenetics, 9052 Gent, Belgium). The HCV RNA < 600 000 IU/ml was considered as low viremia level and > 600 000 IU/ml – as high. According to Lithuanian guides just qualitative HCV test was performed for naive patients with genotype 2 and 3

[12–14]. Viral load before and during treatment course for those patients was not required. Routine biochemical parameters – ALT, AST, ALP and γGT activity, tests for evaluation functional liver capacity (bilirubin and albumin concentration, prothrombin index) and immunological parameters for exclusion of autoimmune hepatitis (serum IgA, IgG, IgM-by immunoassay; autoantibodies ANA and AMA - by immunofluorescence) and serological markers of HBV infection (HBsAg, anti HBc, anti HBs, anti HBe – by „Abbott EIA“ commercial tests) for exclusion of hepatitis B infection were carried out too. Ultrasound and Histology Evaluation All patients underwent ultrasound examination by LOGIQ500 PRO series (General Electric, Yokogava Medical System, Yokogawa, Japan). Echo-guided liver biopsy was performed in the most patients – 197 (97 %) and it was eliminated only because of contraindications. Histological

Patients n=203 M n=107 (52.7 %)

F n=96 (47.3%)

NAIVE n=125 (61.6%)

EXPERIENCED n=78 (38.4%)

M n=56 (44.8%); F n=69 (55.2%)

M n=51 (65.4%); F n=27 (34.6%)

F1-3 n=107 (85,6%)

F3-4 and 4 n=18 (14,4%)

F1-3 n=51 (65,4%)

F 3-4 and 4 n=27 (34,6%)

Discontinuation n=7 (6.5%)

Discontinuation n=0 (0%)

Discontinuation n=2 (3.9%)

Discontinuation n=2 (7.4%)

Fig. 1. Patients groups (by intention to treat analysis/ITT) teorija ir praktika 2015 - T. 21 (Nr. 1)

25

moksliniai tyrimai

evaluation of biopsy specimens was carried out at the National Center of Pathology (accredited by the Association of American Pathologists in 2000 year). Necroimflammatory activity and histological activity index (HAI) was scored according to Ishak et al. (1995) [22], while fibrosis (F) – according to METAVIR scoring system (1994) [23]. Treatment Patients were treated with combination of PegIFN alfa-2a or 2b and RBV according to the Lithuanian guide “Lėtinio virusinio C hepatito diagnostikos ir ambulatorinio gydymo kompensuojamaisiais vaistais metodika” („Methodology of diagnosis and therapy of chronic viral hepatitis C and C liver cirrhosis for reimbursement by health care insurance“ certified in 2003 years (updated in 2005 and 2008) [12–14]. The main inclusion criteria for antiviral Table 1. Characteristics of patients at baseline (ITT)

Male (n/%) Female (n/%) Age (range), years M±m • < 50 (n/%) M±m • > 50 (n/%) M±m ALT/range, U/L M±m AST/range, U/L M±m γGT/range, U/L M±m Biopsy n (%) HAI (M ± m) • 1–3 • 4–8 • 9–12 Fibrosis score (M ± m) • F 1, 1–2 • F 2, 2–3 • F 3,3–4, 4 Steatosis (n/%) • < 30 % • > 30 % • without steatosis

Naive n = 125 (61,6 %) 56/44,8 69/55,2 19–77 45,8 ± 14,0 83 (66,4) 38,0 ± 9,4 42 (33,6) 61,4 ± 6,7 14–845 114,6±121,0 16–252 66,0 ± 43,2 5–264 61 ± 52,7 123 (98,4) 5 ± 1,6 6 (4,8) 108 (86,4) 8 (6,4) 2,4 ± 0,7 10 (8) 98 (78,4) 14 (11,2)

Treated n = 78 (38,4 %) 51/65,4 27/34,6 21–74 52,0 ± 13,0 36 (46,2) 40,3 ± 8,0 42 (53,8) 62 ± 6,3 14–744 110,8±110,9 15–385 90,5 ± 71,2 10–293 70,4 ± 51,3 76 (97,4) 5,6 ± 2,1 10 (12,8) 55 (70,5) 10 (12,8) 2,9 ± 0,9 5 (6,4) 44 (56,4) 26 (33,3)

122 (97,6) 53 (43,4) 15 (12,3) 54 (44,3)

74 (94,9) 26 (35,1) 7 (9,5) 41 (55,4)

Overall n = 203 107/52,7 96/47,3 19–77 48,2 ± 13,9 119 (58,6) 38,7 ± 9,0 84 (41,4) 61,7 ± 6,5 14–845 113,2±117,0 15–385 75,2 ± 56,4 5–293 64,2 ± 52,3 199 (98) 5,2 ± 1,8 16 (8,1) 163 (82,7) 18 (9,1 ) 2,6 ± 0,8 15 (7,6 ) 103 (52,3) 79 (40,1) 196 (96,6) 79 (40,3) 22 (11,2) 95 (48,5)

Genotype (n/%) •1 •2 •3 HCV RNR (n/%) • < 600 000 IU/ml • > 600 000 IU/ml 26

94 (75,2) 7 (5,6) 24 (19,2) 104 (83,2) 33 (31,7) 71 (68,3)

60 (76,9) 3 (3,9) 15 (19,2) 60 (77) 19 (31,7) 41 (68,3)

154 (75,9) 10 (4,9) 39 (19,2) 164 (80,8) 52 (31,7) 112 (68,3)

treatment indicated in Lithuanian guidelines of 2003 and 2005 years were: • persistently or intermittently increased ALT and/or AST activity for 6 months; • histological evidence of CHC or cirrhosis (LC); • HAI ≥ 4 scores (according to Ishak), fibrosis ≥ 2 scores (according to METAVIR); • absence of contraindications for antiviral treatment with Peg IFN and RBV; Treatment Schedule PegIFN alfa-2a (Pegasys) was given at a unique dose 180μg to all patients, while PegIFN alfa-2b (PegIntron) dose was adjusted to the patient’s body weight – 1,5μg/kg weekly in combination with RBV (Copegus or Rebetol). The RBV dose was also adjusted to the body weight: in patients with the weight less than 65 kg, the dose was 800 mg daily, for 66–85 kg patients – 1000 mg, for those with a weight 86 kg and equal or more 100 kg – 1200 mg daily. Participants being on treatment were examined every month on an outpatient’s basis. According to Lithuanian guides (2003–2008 years), treatment course lasted 24 weeks for naives with genotype 2 and 3 and genotype 1 patients with low viremia ( if HCVRNA in the last ones becomes negative after 4 weeks of therapy); for naive genotype 1 patients with high viremia and all experienced ones, irrespective to genotype, duration of therapy – 48 weeks [12–14]. Treatment had to be withdrawn whenever HCV RNA load after 12 weeks decreased less than 2 log from baseline level or found positive after 24 weeks of therapy. Assesment of efficacy The primary measure of efficacy was SVR (sustained virological response), defined as HCV RNA not detectable in serum 24 weeks after the end of therapy. In addition, we evaluate virological response at the end of treatment (EVR) (HCV RNA not detectable at the end of treatment). Statistical analysis The statistical analysis was descriptive to reflect the clinical routine as intended by the clinicians. Data are presented as the percentage or the mean ± standard deviation (SD). Univariate and multivariate logistic regression analyses were applied to test independent variables known from the literature to be associated with the response. All variables reaching a P-value of P < 0.1 in the univariate analysis were then tested for significance by multivariate logistic regression analysis. Analysis of variables was performed by Student's ˝t˝ test (SPSS statistical analysis version 17.0 software for Windows). Differences were considered significant if p 600 000 IU/ml – in 100 (55,9 %) of HCV patients overall. AST, ALT and γGT liver enzymes activity fluctuated in a very wide range: from normal to 10 (ALT), 22 (AST) and 8,5 (γGT) times higher than UNL. Liver biopsy was performed in 175 (97,8 %) patients: 36 (20,1 %) of them had F3 – 4 and F 4, and the majority 138 (77,1 %) − F1, F2 and F2-3 fibrosis stages. The mean fibrosis stage (± SD) was 2,56 ± 0,8. The mean (± SD) histological activity index (HAI) – 5,2 ± 1,8 scores. Steatosis of different grade was found in 51,4 8 % of biopted patients: steatosis less than 10 % prevailed in patients with genotype 1 and 2 (in 62 % and 75 %, respectively), whereas greater than 10 % – in patients with genotype 3 (in 90 %, p < 0,001). Steatosis was statistically significantly related to HAI (p = 0,037), while the latter correlated directly with fibrosis stage: the higher HAI, the greater stage of fibrosis (p = 0,003). In 68,75 % of patients having HAI > 9 scores higher fibrosis stage (F3 4) was found (p = 0,003) (Fig. 2).

Table 2. SVR in naive and treatment experienced patients in relation with different variables (PP analysis) Variables Male Female Age • < 50 • > 50 HAI • 1–8 • 9–12 Fibrosis score • F 1,2 • F 3, 4 Steatosis • < 30 % • > 30 % Genotype •1 •2 •3 HCV RNR • < 600000 IU/ml • > 6000000 IU/ml teorija ir praktika 2015 - T. 21 (Nr. 1)

SVA-Naive n – 115/% 29/60,4 30/44,8 47/61,8 12/30,8 53/51 5/62,5 46/61,3 11/29,7 23/48,9 10/71,4 33/38,8 7/100 19/82,6 15/46,9 28/44,4

P-value 0,071

0,001 0,399

0,006 0,086

0,000 0,496

SVA-Treated n – 64/% 26,7 31,6 33,3 23,5 71,4 25,0 33,3 4,5 18,2 28,6 17 33,3 64,3 20 29,7

P-value 0,455

0,277 0,607

0,058 0,488

0,003 0,481

27

moksliniai tyrimai

Results of Treatment with Pegylated Interferon and Ribavirin In the ITT analysis the overall rate of sustained virological response (SVR) was 39,4 % (80/203): 28,6 % in genotype 1, 80 % in genotype 2 and 71,8 % in genotype 3 patients. In naive patients it was 47,2 % and in treatment experienced – 27 %. The SVR was achieved in 35,1  % (33/94) of naives with genotype 1, in 100 % (7/7) with genotype 2 and in 79,2 % (19/24) with genotype 3. Meanwhile in experienced patients with genotypes 1, 2 and 3 SVR was found in 18,3 %, 33,3 % and 60 %, accordingly. All treatment results and correlations in this article will be presented as per protocol. (Table 2 and 3). The overall ETR was observed in 55,3 % (99/179) patients: in 66,1 % of naive and in 35,9 % of previously treated ones. The overall rate of SVR was 43 %: in 31,1 % of genotype 1 patients, 80 % – genotype 2 and 75,7 % – genotype 3. The SVR occurred in 51,3 % of naive and in 28,1 % of previously treated patients. In naive genotype 1 patients SVR was achieved in 38,8 % cases, genotype 2 – in 100 % and genotype 3 – in 82,6 % SVR rate of experienced patients was significantly lower: in 17 %, 33,3 % and 64,3 % of cases, accordingly (Table 2). In the univariate and multivariate statistical analysis significant relations of SVR and HCV genotype was observed: 68,9 % of patients having genotype 1 were non-responders, whereas 80 % and 75,7 % ones with genotype 2 and 3, respectively, achieved SVR: OR 9.871 (2.013–48.403), p < 0,005 and OR 16.289 (1.954–135.801); p =0.01, respectively) (Table 3 and Fig. 2). This relation was statistically significant in both treated patients groups – naive and treatment experienced. Inverse correlation of SVR rate with the patients age was confirmed by univariate and multivariate analysis: OR 3.896 (1.578–9.616, p = 0.003) and OR 4.48 (1.422– 14.112, p < 0,001). (Table 3). It was especially evident in

naive patients, who SVR was significantly higher (twice) in those younger than 50 years of age compared with the older ones. Overall 69.2 % of patients older than 50 did not respond to the treatment (p < 0,001). However no statistically significant correlation of SVR and age was observed in treatment experienced patients (Table 3). No significant SVR difference between males and females was found too. Moreover SVR of naive females overall and those with genotype 1 was even lower than in males. However it was not statistically significant. Inverse relation of SVR with the degree of fibrosis was observed in univariate and multivariate statistical analysis: the higher fibrosis stage, the lower SVR rate was achieved (54 % in F1-2 vs 25 % in F3-4 patients): OR 11.333 (1.780–72.169; p =0,01) and OR 16.348 (1.146–233.145; p =0,039). No correlations of SVR with HAI, ALT activity, grade of steatosis and viral load were found neither by univariate nor multivariate analysis. Weak trend of inverse SVR correlation with γGT activity was observed by univariate analysis (OR 2.242 (0.956–5.259), p = 0,063), but it was not confirmed by multivariate one. Antiviral treatment after previous unsuccessful course is strong negative predictor for achieving SVR [OR 7.037 (1.970–25.134), p = 0,003 and OR 7.370 (1.368–39.713), p = 0,002]. DISCUSSION Peginterferon plus ribavirin combination therapy up to 2011 was the current standard of care in treatment patients with CHC [6, 9–11]. Three large industry-sponsored, multinational, phase III, randomized-controlled clinical trials (RCTs) have found that combined treatment with pegylated interferon (PEG-IFN) α-2a or α-2b and ribavirin leads to a SVR in 54–63 % of treatment naive CHC patients: about 40–45 % in patients with genotype 1 and 75–80 % in genotypes 2 and 3 [24–26]. Meanwhile, in those who had failed to respond to prior treatment with interferon

Table 3. Correlations of SVR with different variables by univariate and multivariate logistic regression analysis OR, odds ratio; CI, confidence interval; γGT, gamma – glutamyl transferase; ULN, upper limit of the normal range.Variable Age > 50 yrs < 50 yrs γGT level: normal vs (≤ 3x ULN) γGT level: normal vs (> 3x ULN) Fibrosis: 1 vs 2–3 Fibrosis: 1 vs 4 Genotype 1 vs genotype 2–3 Steatosis: < 10 % vs 10–30 % Steatosis: < 10 % vs > 30 % Treatment experienced vs naive patients

Non-responders Univariate analysis

Multivariate analysis

OR (95 % CI)

p-value

OR (95 % CI)

p-value

3.90 (1.58–9.62) 2.24 (0.96–5.26) 1.67 (0.52–5.34) 3.13 (0.73–13.39) 11.33 (1.78–72.17) 9.87 (2.01–48.40) 2.03 (0.85–4.83) 0.50 (0.14–1.76) 7.04 (1.97–25.13)

0.003 0.063 0.390 0.125 0.010 0.005 0.110 0.280 0.003

4.48 (1.42–14.11) 1.33 (0.45–3.95) 2.00 (0.33–12.23) 3.13 (0.63–15.65) 16.35 (1.15–233.15) 16.29 (1.95–135.80) 1.58 (0.51–4.86) 0.09 (0.01–1.62) 7.37 (1.37–39.71)

0.01 0.614 0.455 0.166 0.039 0.01 0.427 0.090 0.002

OR, odds ratio; CI, confidence interval; γGT, gamma – glutamyl transferase; ULN, upper limit of the normal range. 28

teorija ir praktika 2015 - T. 21 (Nr. 1)

moksliniai tyrimai

alone or in combination with ribavirin and were re-treated with pegylated interferon and ribavirin, the response rate was significantly lower, ranging from 20 to 40 % (28 %) and from 8 to 12 %, accordingly [27–29]. Pretreatment predictors of the response are useful for advicing patients on their likelihood of an SVR. So far, numerous factors, including host-, virus- and treatment-related elements have been identified as significant predictors of SVR or non SVR [6, 24–26, 29–31]. Patients infected with “easy-to-treat” genotypes 2 and 3 respond much better than those with “difficult-to-treat” genotypes 1 and 4. HCV genotype, pretreatment viral load, ethnicity, gender, presence of cirrhosis or advanced fibrosis, obesity, steatosis, insulin resistance, elevated γGT and other are significantly associated with the outcome of Peg-IFN plus RBV combination therapy [32, 34–38]. Furthermore, those with low pretreatment viral load respond much better than those with high pretreatment viral load. Data on predictors usually comes from RCT and are the basis for the development of clinical guidelines and for decisions regarding patient management. However RCT results on antiviral treatment outcomes as well as predictors of its efficacy may not reflect the results in routine clinical practice, and studies carried out in ‘true life’ are needed to confirm these conclusions. In clinical practice we treat ‘real patients’ and cannot select the best candidates for treatment, as in RCT. Additionally, there is possible that the treatments efficacy given in clinical trials may be affected by greater patient⁄doctor motivation and⁄or closer supervision than that feasible in routine clinical practice [32, 36]. Moreover efficacy of the treatment may be reduced by the treatment discontinuation because of side-effects which may be higher than in RCT [37]. Aiming to clarify the treatment outcomes and efficacy of combined therapy with peginterferon and ribavirin in treatment naive and treatment experienced HCV patients, and to evaluate possible predictors of SVR we carried out retrospective analysis of the data obtained in routine clinical practice. The reports on the „true life” treatment results with pegylated interferon and ribavirin of HCV infected patients are controversial. Some studies showed SVR similar to that obtained during RCT. Danish nationwide cohort study [38], presented the data obtained in a routine clinical practice and found them comparable to those observed in controlled clinical trials: overall 57.9 % of patients achieved SVR: it was 46.5 % in patients with genotype 1/4 infection and 77.3 % in those with genotype 2/3 infection. Some other authors [39–45] and community based studies in Germany, Canada, France and Australia [46–51] reported SVR data comparable with those in RCT too. Conversely, results of other investigators were lower [52, 53]. Retrospective, observational cohort study in US veterans population also found significantly lower SVR rates, than in clinical trials ie teorija ir praktika 2015 - T. 21 (Nr. 1)

20 %, 52 % and 43 % in genotypes 1, 2 and 3, respectively [19]. The authors concluded that clinicians should not assume that results from registration trials are transferable to their own clinical practice. The lower SVR rate (37.5 %) of patients in “real life“ treatment study and low eligibility to therapy at general population level in a highly endemic area was presented by Mariano et al (2009) and in nationwide retrospective treatment study in Hungary [54, 55]. In our study overall sustained virological response in ITT/PP analysis was achieved in 39,4 % /43 % patients: in 47,2 % / 51.3 % of naive and 26.9 % / 28.1 % of treatment experienced patients, respectively. Among naive patients, the SVR was 35,1 % / 38.8 % in genotype 1, 100 % / 100 % – in genotype 2, 79,2 % / 82,6 % – in genotype 3 patients; and in 18,3 % / 17 %, 33,3 % / 33 % and in 60 % / 64,3 % of treatment experienced patients in per ITT/PP analysis, accordingly. Our data of SVR in per protocol analysis did not differ significantly from those in ITT, so further only the results obtained in per PP analysis will be discussed. Rather low overall SVR of our patients might be explained by the specific features of the treatment experienced patients subgroup which comprised actually 38 % of the overall group, most of them were males (70,3 %), with prevalence of older ones (over 50). Moreover 53,1 % and 34,6 % of them had advanced fibrosis and cirrhosis (F3-4 and F4). There is well known and confirmed by other investigators that above-mentioned patients population usually showed significantly lower SVR rate than naives, more younger ones, females and those without advanced fibrosis or cirrhosis [24–26, 33, 42, 56]. The treatment results of naive patients in our study correspond with the data of some „real life“ studies – German multicenter open label study and Canadian Power program, being slightly lower in genotype 1 and higher in genotype 2 and 3 patients [45, 48]. SVR of naive patients overall and those with genotype 1 were also very similar to the results presented in classical clinical trial carried out by Manns, but higher for patients with genotype 2 and 3 (91,3 % and 82,76 % vs 80 %)[25]. When comparing SVR results of our patients with genotype 1 with the data obtained in other RCT and community based studies carried out in Europe and USA they were slightly lower (38,8 % vs 46 % and 52 %) [24, 26, 48, 50]. The overall SVR of treatment experienced patients in our study was 43 % and differed significantly depending on genotype: it was very low for genotype 1 patient (17 %), but rather high in those with genotype 3 (64,3 %). Just three previously unsuccessfully treated patients with genotype 2 were treated repeatedly and SVR was achieved in 2 of them. Previous treatment was performed with standard interferon alfa 2b and ribavirin mostly (in 2/3 of patients) or with interferon monotherapy and combination of peginterferon plus ri29

moksliniai tyrimai

bavirin in the other third of patients. Low SVR of treatment experienced genotype 1 patients is in accordance with the data of other investigators [50, 57–60] and are very similar to the findings obtained in observational French study: they found SVR 39 % in ITT population: 43 % in naive and 31 % in treatment-failure patients, but was lower in comparing with the results of others [61]. HCV genotypes are considered as the strongest baseline predictors for response for dual therapy and our data confirmed that: HCV genotype 1 is the major negative predictor of SVR – “difficult to treat genotype“ by univariate and multivariate analysis. Almost 70 % of patients having genotype 1 were non-responders, whereas 80 % and 75,7 % of those with genotype 2 and 3 ”easy-totreat“ ones, respectively, responded well. Our results regarding genotypes as the strong predictors of SVR correspond to the data of the majority of other investigators obtained in RCT and in “real life” studies [10, 24, 25, 28, 31, 32, 33, 40, 42, 46, 48–50]. The inverse correlation of SVR with the patients age was detected too and confirmed by univariate and multivariate analysis. It was evident in naive patients subgroup especially, where SVR was twice as high in those younger than 50 years compared with the older ones. Overall 69,2% of naive patients over 50 did not respond to the treatment (p < 0,001). Inspite of the same SVR trend in treatment results of experienced patients inverse correlation with the age was weak and statistically not significant. Our data confirmed that older age increases the risk of primary treatment failure and correspond to the data of other investigators who found inverse relation of age and SVR [24–27, 31–34, 40, 44, 45, 61, 56]. Majority of RCT and community based studies found that high pretreatment viral load and presence of advanced fibrosis or cirrhosis are strong independent negative predictors of SVR in combined antiviral treatment [15, 24, 25, 40, 44, 45–62]. Our data also confirmed the advanced fibrosis and cirrhosis as the strong negative predictors of SVR: the higher fibrosis stage the lower SVR rate was achieved SVR of naive and treatment experienced patients with F1-2 was almost twice and seven times higher, accordingly, than in those with advanced fibrosis and cirrhosis (F3 and F4). Statistically significant correlations with viral load were not found either in naive or in experienced treatment patients. Some differences of SVR between males and females were observed, but statistical analysis did not confirm female gender as significant positive predictor of SVR neither by multivariate nor univariate analysis. Naive females in our study showed even lower SVR than males (60,4 % vs 44,8 %, p < 0001). Possible reason – females were older than males. There are contradictory data regarding impact of female gender on antiviral treatment outcome. Some investigators 30

found female gender as the positive predictor for SVR in RCT and in “real life condition”studies [9, 24, 25, 56, 63, 64]. The others did not confirm these results [20,40,42,44,65], or even found that response to combined treatment and SVR in females 50 years old or older was poorer than in males [66]. Low estrogens level in older women could be responsible for their impaired response to antiviral treatment. Steatosis of different grade was found in 51,4 8 % of our biopted patients: steatosis less than 10 % prevailed in patients with genotype 1 and 2 , whereas it was greater than 10 % – in patients with genotype 3 (in 90 %, p < 0,001). No correlations of SVR with steatosis and its grade were found neither by univariate nor multivariate analysis. Several investigators reported that increased γGT activity strongly associates with primary antiviral treatment failure [21, 64, 67–69]. Weak trend of inverse SVR correlation with γGT activity was found in our study by univariate analysis too [OR 2.242 (0.956–5.259), p–0,063], but it was not confirmed by multivariate analysis. We also found no correlations of SVR with HAI and ALT activity neither by univariate nor multivariate analysis. Data regarding those variables are contradictory: some investigators found positive predictivity of ALT activity higher than 3 times UNL and higher HAI scores for SVR [44, 59, 72, 73], the others did not confirm any correlation of ALT and SVR [70]. Our data confirmed that antiviral treatment after previous unsuccessful course is strong negative predictor for achieving SVR by univariate and multivariate analysis, accordingly [OR 7.037 (1.970–25.134, p–0,003) and OR 7.370 (1.368–39.713, p–0,002)]. IN CONCLUSION Results of SVR obtained in our study „on real life“ conditions are non unambiguous: SVR of naive patients overall and those with genotype 1 were similar or slightly lower while for patients with genotype 2 and 3 higher than results presented in RCT. The same trend of SVR was observed in treatment experienced patients too: as compared with data of clinical studies SVR was lower in genotype 1 patients, but higher in genotype 3. The strongest negative predictors for SVR were genotype 1, previous unsuccessful course of antiviral treatment, older age (>50yrs), and advanced fibrosis and cirrhosis. REFERENCES

1. Bialek SR, Terrault NA. The changing epidemiology and natural history of hepatitis C virus infection. Clin Liver Dis. 2006; 10: 679. 2. Ambrozaitis A. Infekcinių ligų vadovas. Vilnius: UAB „Vaistų žinios“; 2010, 494–521. 3. Liakina V, Valantinas J. Anti-HCV prevalence in the general population of Lithuania. Med. Sci. Monit 2012 Mar; 18(3): PH 28–35. teorija ir praktika 2015 - T. 21 (Nr. 1)

moksliniai tyrimai 4. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011; 364: 1195–1206. 5. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011; 364(25): 2405–16. 6. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. Journal of Hepatology. 2014; 60: 392–420. 7. EASL Recommendations on Treatment of Hepatitis C 2014 April. Available from: http://www.easl.eu/ 8. AASLD and IDSA Recommendations for Testing, Managing, and Treating Hepatitis C. 2013 December. Available from: http://www.hcvguidelines.org. 9. National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: 2002. Hepatology. 2002; 36(Suppl 1): S3. 10. AASLD Practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C. Hepatology. 2009; 49(4): 1335–1374. 11. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. Journal of Hepatology. 2011; 55: 245–264. 12 Lėtinio virusinio hepatito C ir virusinės C kepenų cirozės diagnostikos bei ambulatorinio gydymo, kompensuojamo iš Privalomojo sveikatos draudimo fondo biudžeto, metodika: patvirtinta Privalomojo sveikatos draudimo tarybos posėdyje, 2003 m. rugsėjo 23 d. Lietuvos Respublikos sveikatos apsaugos ministro įsakymas Nr. V-652 (Žin. 2003, Nr. 108–4861). 13. Dėl lėtinio virusinio hepatito C ir virusinės C kepenų cirozės diagnostikos bei ambulatorinio gydymo, kompensuojamo iš Privalomojo sveikatos draudimo fondo biudžeto, metodikos patvirtinimo „pakeitimo“. Lietuvos Respublikos sveikatos apsaugos ministro 2005 m. rugsėjo 9 d. įsakymas Nr. V-689 (Žin. 2005, Nr. 111-4059). 14. Dėl lėtinio virusinio C hepatito diagnostikos ir ambulatorinio gydymo kompensuojamaisiais vaistais tvarkos aprašo tvirtinimo. Lietuvos Respublikos sveikatos apsaugos ministro 2008 m. birželio 20 d. įsakymas Nr. V-613 (Žin. 2008, Nr. 74-2897). 15. Shiffman ML. Treatment of Hepatitis C in 2011: What Can We Expect? Curr Gastroenterol Rep. 2010; 12: 70–75. 16. Tsung-Ming Chen, Pi-Teh Huang,Ching-Heng Lin, Ming-Hung Tsai, Lien-Fu Lin, Chung- Cheng Liu, et al. Feasibility of individualized treatment for hepatitis C patients in the real world. Journal of Gastroenterology and Hepatology. 2010; 25: 61–69. 17. Borroni G, Andreolleti M, Casigrahi MA, Ceriani R, Guerzoni P, Omazzi B, et al. Effectiveness of pegylated interferon⁄ribavirin combination in “real world” patients with chronic hepatitis C virus infection.Aliment Pharmacol Ther. 2008; 27(9): 790–797. 18. Marcellin P, Chousterman M, Fontanges Th, Ouzan D, Rotily M, Varastet M, et al. Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study. Liver Int. 2011; 31(4): 516–24. 19. Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology. 2007; 46: 37–47. 20. Hansen N, Obel N, Christensen PB, et al. Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study. BMC Infectious Diseases. 2011; 11: 177. 21. Mauss S, Hueppe D, John C, Goelz J, Heyne R, Moeller B, et al. Estimating the Likelihood of Sustained Virological Response in Chronic Hepatitis C Therapy. J Viral Hepat. 2011; 18(4): e81–e90. 22. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995; 22: 696–9. 23. METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology. 1994; 20: 15–20. teorija ir praktika 2015 - T. 21 (Nr. 1)

24. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347: 975–82. 25. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001; 358: 958–65. 26. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P et al. et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. . Ann Intern Med 2004; 140: 346–55. 27. Shiffman ML, Lindsay KL, Di Bisceglie AM, Morishima C, Wright EC, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who failed prior treatment. Gastroenterology. 2004; 126: 1015–1023. 28. Poynard T, Colombo M, Bruix J,Schiff E, Terg R, Flamm S. et al. Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa⁄ribavirin therapy. Gastroenterology. 2009; 136: 1618–28. 29. Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006; 131: 470–477. 30. Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, Wedemeyer H, et al. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat. 2009; 16(2): 75–90. 31. Berg T, Sarrazin C, Herrmann E, Hinrichsen H., Gerlach T, Zachoval R, et al. Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology. 2003; 37: 600–609. 32. Conjeevaram HS, Kleiner DE, Everhart JE, Hoofnagle JH, Zacks S, Afdhal NH, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007; 45: 80–87. 33. Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL Jr, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol. 2005; 43: 425–433. 34. Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Vallée M, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol. 2004; 40: 484–490. 35. Asselah T. ,Estrabaud E, Bieche I, Lapalus M, De Muynck S, , et al. Hepatitis C: viral and host factors associated with nonresponse to pegylated interferon plus ribavirin. Liver Int. 2010; Oct; 30(9): 1259–69. 36. Gaeta GB, Precone DF, Felaco FM, Bruno R, Spadaro A. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in real world patients with chronic hepatitis C. Aliment Pharmacol Ther. 2002; 16: 1633–1639. 37. Borroni, M. Andreolleti, M. A. Casigrahi. Effectiveness of pegylated interferon ⁄ ribavirin combination in ‘real world’ patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther 2008; 27, 790–797. 38. Hansen N, Obel N, Christensen PB , Kjaer M,LaursenA.R ,Krarup HB et al. and the Danish Database for Hepatitis B and C (DANHEP)-group. Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study. BMC Infectious Diseases, 2011, 11:177. 39. Goncales FL, Moma CA, Vigani AG, Goncales ES, Angerami AF, Tozo R, et al. Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in non-responders to interferon plus ribavirin. Is it different in real life? BMC infectious Diseases, 2010; 10(1): 212. 40. Ridruejo E. Treatment of chronic hepatitis C with pegylated interferon and ribavirin in treatment-naive patients in ‘true life’ Eur J Gastroenterol Hepatol, 2011 Feb., 23(2), 195.

31

moksliniai tyrimai 41. Rizetto M, Colombo M, Ascione A, Piccinino F, Craxi A, Alberti AT, et al. Effectiveness of hepatitis C treatment in real life practice:a prospective observational multicenter study in Italy (PROBE). J Hepatol, 2008,48 (suppl 2): S311. 42. Muller K, Rodgers A, Wundke R, Waddell V, Altus R, Gordon DL, et al. Single centre experience with pegylated interferon and ribavirin for hepatitis C: looking back before moving forward. Intern Med J. 2012 Jul; 42(7): 765–72. 43. Thomson BJ, Kwong G, Ratib S, Sweeting M,Ryde D.,De Angelis et al. Response rates to combination therapy for chronic HCV infection in a clinical setting and derivation of probability tables for individual patient management. J Viral Hepat, 2008; 15: 271–278. 44. Lee SS, Bain VG, Peltekian K, Krajden M, Yoshida EM. Deshenes M et al. Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice. Aliment Pharmacol Ther, 2006; 23: 397–408. 45. Borroni G, Andreoletti M, Casiraghi MA, Ceriani R, Guerzoni P, Omazzi B, et al. Effectiveness of pegylated interferon/ribavirin combination in “real world” patients with chronic hepatitis C virus (HCV) infection. Aliment Pharmacol Ther. 2008; 27: 790–797 Borroni 2008. 46. Witthoft T, Moller B, Wiedmann KH,Mauss S, Link R, Lohmeyer J, et al. Safety, tolerability and efficacy of peginterferon alpha-2a and ribavirin in chronic hepatitis C in clinical practice: the German Open Safety Trial. J Viral Hepat. 2007; 14: 788–79. 47. Witthoeft T, Hueppe D, John C, Goelz J, Heyne R, Moeller B, et al. Efficacy and tolerability of peginterferon alfa-2a or alfa-2b plus ribavirin in the daily routine treatment of patients with chronic hepatitis C in Germany: The PRACTICE Study. Journal of Viral Hepatitis, 2010, 17, 459–468. 48. Zehnter E, Huppe D, BNG Hepatitis Study Group et al. Individualized weight adjusted peginterferon alfa-2b e ribavirin in HCV in the clinical setting: the German experience. Poster presented at the Frontiers in Drug Development for Viral Hepatitis HEP DART 2005, December 11–15, 2005, Kohala Coast, Hawaii. 49. Marotta P, Feinman SV, Ghent C, Scully L, Varenbut M, Daiter J, et al. Final results of the Canadian POWeR (Pegetron Prospective Optimal Weight-based Dosing Response) program: sustained virologic response (SVR) to weight based peginterferon alfa-2b ribavirin in a large, mixed, community and academic observational study. Poster presented at 58th Annual Meeting of the American Association for the Study of Liver Diseases, November 2-6, 2007, Boston, MA. 50. Bourliere M, Ouzan D, Rosenheim M, Doffoel M, Marcellin P, Pawlotsky JM et al. Efficacy of peginterferon alfa-2a and ribavirin in 2102 patients with HCV infection in real-life clinical practice: results of the French HEPATYS study (abstract). Hepatology, 2007; 46(Suppl): 366A. 51. Gidding H, Law MJ, Amin J, Ostapowicz G, Veltman M, et al. Hepatitis C treatment outcomes in Australian clinics. Med J Aust 2012, 196(10): 633–637. 52. de Almeida PR, de Mattos AA, Amaral KM, Feltrin AA, Zamin P, Tovo CV, et al. Treatment of hepatitis C with peginterferon and ribavirin in a public health program. Hepatogastroenterology. 2009 Jan–Feb; 56(89): 223–6. 53. Jacobson IM, Brown RS, Freilich B, Afdhal N, Kwo PY, Santoro J, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology, 2007; 46: 971–981. 54. Mariano A, Caserta C, Pendino GM, Vacalebre C, Surace P, Fiorillo MT, et al. Antiviral treatment for hepatitis C virus infection: Effectiveness at general population level in a highly endemic area. Digestive and Liver Disease. 2009; 41(7): 509–515. 55. Pár A, Tornai I, Szalay S.F. Experiences in antiviral treatment of chronic viral hepatitis B and C in Hungary (1998–2004). Orv Hetil. 2007; 148(18): 819–26.

32

56. Craxi A, Piccinino F, Alberti A, Ascione A, Rizzetto M, Iannacone C et al.Predictors of SVR in naïve HCV G1 patients in real life practice: the PROBE. J Hepatol. 2008; 48:(Suppl 2): S291. 57. Pearlman B, Ehleben C. Retreatment of chronic Hepatitis CGenotype 1-infected Relapsers to Peginterferon/ribavirin with Consensus interferon/ribavirin or with Extended Duration Therapy Peginterferon/ribavirin. AASLD Annual Meeting 2009: Abstract 815. 58. Jensen DM, Marcellin P, Freilich B, Andreone P, Di Bisceglie A, Brandao-Mello CE, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha 2b: a randomized trial. Ann Intern Med, 2009; 150: 528–40. 59. Bacon BR, Shiffman ML, Mendes F,Ghalib R, Hassanein T, Morelli G, et al. Retreating chronic hepatitis C with daily interferon alfacon-1 ⁄ ribavirin after nonresponse to pegylated interferon ⁄ ribavirin: DIRECT results. Hepatology, 2009; 49: 1838–46. 60. Cheruvattath R, Rosati MJ, Gautam M, Vargas HE, Rakela J, Balan V. Pegylated interferon and ribavirin failures: is retreatment an option? Dig Dis Sci, 2007; 52: 732–736. 61. Velosa J, Bana T, Redondo I, Simão A, Vale AM, Pires S, et al. Chronic hepatitis C treated with peginterferon alfa plus ribavirin in clinical practice.Hepatogastroenterology. 2011 Jul–Aug; 58(109): 1260–6. 62. Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology, 2007; 46: 37–47. 63. Floreani A, Cazzagon N, Boemo DG, Baldovin T, Baldo V, Egoue J, et al. Female patients in fertile age with chronic hepatitis C, easy genotype, and persistently normal transaminases have a 100 % chance to reach a sustained virological response. Eur J Gastroenterol Hepatol, 2011; Nov; 23(11): 997–1003. 64. Innes HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Carman B et al. Hepatitis C Clinical Database Monitoring Committee Ranking predictors of a sustained viral response for patients with chronic hepatitis C treated with pegylated interferon and ribavirin in Scotland. Eur J Gastroenterol Hepatol. 2012 Jun; 24(6): 646–55. 65. Narciso-Schiavon JL, Schiavon Lde L, Carvalho-Filho RJ, Sampaio JP, Batah PN et al. Gender influence on treatment of chronic hepatitis C genotype 1. Rev Soc Bras Med Trop. 2010 May–Jun; 43(3): 217–23. 66. Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N et al. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral loads. Dig Dis Sci. 2009; 54: 1317–1324. 67. Coban S, Idilman R, Erden E, Tuzun A. Gamma-glutamyltranspeptidase in predicting sustained virological response in individuals with chronic hepatitis C. Hepatogastroenterology, 2011 Jul–Aug; 58(109): 1301–6. 68. Weich V, Herrmann E, Chung TL, Sarrazin C, Hinrichsen H, Buggish et al. The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection Gastroenterol. 2011 Dec; 46(12): 1427–36. 69. Aziz Hs, Raza A, Waheed Y, Gill U, Gill ML. Analysis of variables and interactions amongvariables associated with a sustained virological response to pegylated interferon alfa-2a plus ribavirin in hepatitis C virus genotype 3-infected patient. Int J Infect Dis. 2012 Aug; 16(8): e597–602. 70. Sieberhagen C, M Brown ASM, Demuth DG, Livingstone JA, Cramp ME PTU-069 Predictors of hepatitis C treatment outcome in genotype 1 patients in a "real world" setting. Gut 2010; 59: A77.

Gautas 2014 m. liepos 11 d., aprobuotas 2014 m. rugsėjo 16 d. Submitted July 11, 2014, accepted September 16, 2014. teorija ir praktika 2015 - T. 21 (Nr. 1)