HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b

  • Adriano M Pellicelli1Email author,

    Affiliated with

    • Mario Romano2,

      Affiliated with

      • Tommaso Stroffolini3,

        Affiliated with

        • Ettore Mazzoni4,

          Affiliated with

          • Fabrizio Mecenate5,

            Affiliated with

            • Roberto Monarca6,

              Affiliated with

              • Antonio Picardi7,

                Affiliated with

                • Maria Elena Bonaventura8,

                  Affiliated with

                  • Cristina Mastropietro9,

                    Affiliated with

                    • Pascal Vignally10,

                      Affiliated with

                      • Arnaldo Andreoli1,

                        Affiliated with

                        • Massimo Marignani11,

                          Affiliated with

                          • Cecilia D’Ambrosio1,

                            Affiliated with

                            • Lucia Miglioresi1,

                              Affiliated with

                              • Lorenzo Nosotti12,

                                Affiliated with

                                • Olga Mitidieri13,

                                  Affiliated with

                                  • Umberto Vespasiani Gentilucci7,

                                    Affiliated with

                                    • Claudio Puoti13,

                                      Affiliated with

                                      • Giuseppe Barbaro14,

                                        Affiliated with

                                        • Angelo Barlattani15,

                                          Affiliated with

                                          • Caterina Furlan3,

                                            Affiliated with

                                            • Giorgio Barbarini16 and

                                              Affiliated with

                                              • and for the CLEO Group

                                                Affiliated with

                                                BMC Gastroenterology201212:162

                                                DOI: 10.1186/1471-230X-12-162

                                                Received: 18 June 2012

                                                Accepted: 13 November 2012

                                                Published: 16 November 2012

                                                Abstract

                                                Background

                                                The impact of viral subtype on the rate of sustained virological response (SVR) to antiviral therapy in patients chronically infected with hepatitis C genotype 1 subtype 1a and 1b has not been extensively investigated. The aim of this study is to determine whether the HCV genotype 1 subtypes 1a and 1b respond differently to treatment with PEGylated interferon (PEG-IFN) plus ribavirin.

                                                Methods

                                                For 48 weeks, 388 “naïve”genotype 1 patients were treated weekly with PEG-IFN α-2a or PEG-INF α-2b combined with daily ribavirin (1000–1200 mg/day). The numbers of patients in whom HCV-RNA was undetectable were compared after 4 (rapid virological response, RVR), 12 (early virological response, EVR), and 48 (end treatment virological response, ETR) weeks of treatment as well as 24 weeks after the last treatment (sustained virological response, SVR).

                                                Results

                                                The rate of SVR was higher in subtype 1a patients than subtype 1b patients (55% vs. 43%; p < 0.02). Multiple logistic regression analysis showed that infection with genotype 1a (odds ratio(OR) : 1.8; 95% confidence interval (CI): 1.4 to 4.1), age < 50 years (OR:7.0; 95% CI 1.1 to 21.2), alanine aminotransferase level (ALT)<100 IU/ml (OR:2.1; 95% CI: 1.3 to3.5), HCV-RNA < 5.6 log10 IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9) and fibrosis score < S3 (OR: 3.8; 95% CI:3.2 to 7.4), were all independent predictors of SVR.

                                                Conclusion

                                                Dual antiviral therapy is more effective against HCV subtype 1a than against subtype 1b and this difference is independent of other factors that may favour viral clearance.

                                                Trial registration

                                                ClinicalTrials.gov Identifier: NCT01342003

                                                Keywords

                                                Genotype 1a HCV genotype 1 subtypes Sustained virological response Antiviral therapy Pegylated interferon

                                                Background

                                                Despite the promise of new antiviral drugs that can act directly on hepatitis C viral replication such as protease and polymerase inhibitors, a 48 weeks course of PEGylated interferon (PEG-INF) combined with ribavirin remains the current standard treatment for genotype 1 chronic hepatitis C (CHC) [1, 2]. Extensive research has shown that patients infected with HCV genotype 1 have a lower rate of viral response than those infected with genotype 2 or 3. In large randomized multinational trials, PEGylated interferon α-2a plus ribavirin has produced an SVR of about 50% in the more difficult-to-treat subgroup of patients infected with HCV genotype 1 [3, 4]. Furthermore, advanced fibrosis is a predictor of non response to antiviral treatment in patients with genotype 1 virus [57]. Very few studies have examined whether the subtype of genotype 1(1a or 1b) affects the rate of SVR [710].

                                                We have performed an observational study on a large cohort of “naïve” HCV patients to evaluate the influence of HCV subtypes 1 on the response to treatment with PEG-INF plus ribavirin.

                                                Methods

                                                Patients

                                                A total of 11 regional centres affiliated with the CLEO Group partecipate in the study between February 2007 and October 2010. Eligible subjects were naïve patients infected with HCV genotype 1 virus who met the internationally recognised criteria for treatment (elevation of aminotransferases and inflammation and/ or fibrosis at liver biopsy). The exclusion criteria included co-infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV), alcohol intake averaging greater than 20 g per day, active drug abuse, chronic systemic disease, psychiatric disorders, autoimmune disease, pregnancy or lactation. The following data were collected: age, gender, body mass index (BMI) and Ishak score of liver biopsy [11]. Of the 388 patients, 322 provided informed consent for liver biopsy.

                                                All patients received Peg-IFN α-2a at 180 μg/week or PEG-INF α-2b at 1.5 μg/kg/week combined with ribavirin at 1000 mg/day if the body weight was < 75 Kg or 1200 mg/day if the body weight was > 75 kg. The dose of PEG-INF and ribavirin were modified as necessary according to the standard criteria and protocol [12]. Patients with undetectable HCVRNA at week 4 were considered rapid virological responders (RVR) and were treated for full 48 weeks. Patients with a < 2 log decline in HCVRNA at week 12 or who remained HCVRNA positive at week 24 were considered to be non-responders and did not continue with the treatment regimen. All patients who withdrew from the study were also defined as non-responders. The primary end point was sustained undetectable serum HCVRNA 24 weeks after the end of treatmen (SVR).

                                                HCVRNA quantification

                                                Quantitative determination of HCVRNA (TaqMan Roche Diagnostics). was performed before the treatment. The TaqMan value used to determine the response was 15 IU/ml. The TaqMan method is a standardised technique that was used in all the CLEO group centres beginning in December 2007. HCVRNA level was expressed as log10 IU/ml. HCVRNA was measured before the treatment, at weeks 4,12,24,48 of treatment and 24 weeks after the final treatment. HCV genotyping was performed using a hybridisation technique (INNOLiPA HCV Immunogenetics).

                                                Statistical analysis

                                                All analysis were performed on the basis of the intention to treat (ITT);i.e., the denominator included all subjects who received at least 1 dose of treatment.

                                                Statistical analysis was performed using the Epiinfo software package. All Data were expressed as the median and range for discrete variables and as counts and percentages for qualitative variables. The differences between the groups were compared using non parametric tests (the Mann Whitney U test for continuous variables and χ2 test for parametric variables). A p value of < 0.05 was considered to be significant.

                                                The crude odds ratios (O.R s) for the association of SVR with different variables were evaluated by univariate analysis. The following variables were analyzed: sex, age (cut-off 50 years), ALT (cut-off 100 IU/ml), gamma-glutamyltranspeptidase (GGT), BMI (cut-off 24.9), HCV-RNA (cut-off 400,000 IU/ml), HCV genotype 1 subtype ( 1a or 1b), liver biopsy grade and stage score, and type of PEGylated interferon received. The adjusted O.R. were calculated by multiple logistic regression analysis in order to identify independent predictors of SVR. Adjustment were made for all of the variables considered at univariate analyses.

                                                Ethics

                                                The study was approved by a central ethic committee (San Camillo Hospital Rome Italy).

                                                Results

                                                The study included 388 patients; of these 165 were infected with HCV genotype 1 subtype 1a (42.5%) and 223 with subtype 1b (57.5%). On average, subtype 1a patients were younger and had lower baseline HCV-RNA levels than subtype 1b patients. All the baseline characteristics of the 388 patients are reported in Table  1.
                                                Table 1

                                                Baseline Characteristics of study population according to HCV subtype

                                                 

                                                Genotype 1a (n = 165)

                                                Genotype 1b (n = 223)

                                                P value

                                                Sex (M/F)

                                                120/45

                                                123/100

                                                0.001

                                                Age (y)

                                                45.0 ± 10.6

                                                49.0 ± 12.1

                                                0.0001

                                                BMI (kg/m2)

                                                24.1 ±  3.2

                                                24.0 ± 3.3

                                                ns

                                                ALT (IU/ml)

                                                109.2 ± 68.7

                                                101.4 ± 61.2

                                                ns

                                                GGT (IU/ml)

                                                65.1 ±  39.1)

                                                67.3 ± 54.5

                                                ns

                                                Hgb (gr/dL)

                                                15.2 ± 1.3

                                                14.8 ± 1.9

                                                ns

                                                HCV-RNA ( log10 IU/ml)

                                                5.72 ± 0.7

                                                5.9 ± 0.5

                                                0.006

                                                HCV-RNA n (%)

                                                   

                                                ≤ 5 .60 log10

                                                52 (32)

                                                44 (20)

                                                0.01

                                                > 5 .60 log10

                                                113 (68)

                                                179 (80)

                                                0.01

                                                Staging n (%)

                                                   

                                                ≤ S3

                                                111 (85)

                                                151 (79)

                                                ns

                                                > S3

                                                19 (15)

                                                41 (21)

                                                ns

                                                Source of Infection n (%)

                                                   

                                                -BT

                                                69 (41)

                                                85 (38)

                                                ns

                                                -DA

                                                78 (47)

                                                92 (41)

                                                ns

                                                -S

                                                8 (5)

                                                15 (7)

                                                ns

                                                -UN

                                                11 (7)

                                                32 (14)

                                                0.03

                                                Legend: M: male, F: female, y:years, BMI: body mass index, ALT: alanine aminotransferase value, GGT: gamma-glutamiltranspeptidasi, Hgb:Haemoglobin value, BT: blood trasfusione, DA:drug abuse, S: sexual, UN: unknown.

                                                Virological response

                                                At week 4 of treatment HCV-RNA was undetectable (RVR) in 77 genotype 1a patients (47%) and in 83 genotype 1b patients (37%) ( p < 0.07). At week 12 of treatment 91 genotype 1a patients (55%) and 99 genotype 1b patients (44%) had undetectable HCV-RNA (early virological response; EVR) (p < 0.04). At the end of treatment 108 genotype 1a patients (65%) and 131 genotype 1b patients (58%) had undetectable HCV-RNA (p = n.s). Seventeen (10%) of the genotype 1a patients and 32 (14%) of the genotype 1b had detectable HCVRNA at week 12 but not at week 24 (slow responders) (p = ns).At the end of the treatment, there were 16 (9%) relapsed patients in the genotype 1a group and 35(15%) in the genotype 1b group (p = ns). Sustained virological response was attained in 91 genotype 1a patients (55%) and 96 genotype 1b patients (43%) ( p < 0.02). A total of 18 genotype 1a and 16 genotype 1b patients discontinued all treatments at some time during the study owing due adverse events (Figure  1).
                                                http://static-content.springer.com/image/art%3A10.1186%2F1471-230X-12-162/MediaObjects/12876_2012_826_Fig1_HTML.jpg
                                                Figure 1

                                                Rapid virological response (RVR), early virological response (EVR), end treatment virological response (ETR), sustained virological response (SVR) and drop out in genotype 1 subtypes 1a and 1b patients.

                                                Sustained virological response

                                                The overall rate of SVR was 48.2%. Subtype 1a, age < 50 years, ALT value < 100 IU/ml, HCV-RNA < 400.000IU/ml (< 5 .60 log10 IU/ml), and fibrosis score ≤ S3 were all factors predisposing to SVR (Table  2). The rate of SVR in patients with fibrosis score S0-S3 was significantly higher for subtype 1a (62%) than for subtype 1b (48%) ( p < 0.03); while no statistically significant difference in SVR was observed between the 2 subtypes (1a and 1b) in patients scoring S4-S6 (31.5% vs. 28%; p = n.s.).(Data not shown).
                                                Table 2

                                                Overall SVR according to different variables

                                                Variable

                                                N° of pts/Tot pts

                                                SVR (%)

                                                P value

                                                Sex

                                                   

                                                F

                                                68/145

                                                46

                                                ns

                                                M

                                                119/243

                                                49

                                                 

                                                Age

                                                   

                                                < 50

                                                123/210

                                                58

                                                0.00001

                                                > 50

                                                64/178

                                                37

                                                 

                                                BMI

                                                   

                                                < 25

                                                145/280

                                                51

                                                0.05

                                                > 25

                                                32/82

                                                39

                                                 

                                                ALT

                                                   

                                                < 100

                                                139/261

                                                53

                                                0.002

                                                > 100

                                                51/127

                                                40

                                                 

                                                HCV-RNA

                                                   

                                                ≤ 5 .60 log10

                                                64/96

                                                66

                                                0.00004

                                                > 5 .60 log10

                                                123/292

                                                42

                                                 

                                                Genotype

                                                   

                                                1a

                                                91/165

                                                55

                                                0.02

                                                1b

                                                96/223

                                                43

                                                 

                                                Staging*

                                                   

                                                ≤ S3

                                                142/262

                                                54

                                                0.00008

                                                > S3

                                                15/60

                                                25

                                                 

                                                Drug

                                                   

                                                PegINF α 2b

                                                100/195

                                                51

                                                ns

                                                PegINF α 2a

                                                87/193

                                                45

                                                 

                                                RVR

                                                   

                                                Yes

                                                129/160

                                                80

                                                0.000001

                                                No

                                                58/228

                                                25

                                                 

                                                Legend. SVR: sustained virological response, F: female, M:male, PegINF: pegylated interferon, BMI: body mass index, ALT: alanine aminotransferase value (IU/ml); RVR: rapid virological response.

                                                *322 over 388 patients were submitted to liver biopsy and analyzed for this variable.

                                                Table  3 shows the crude and adjusted Odds Ratios (ORs) for the associations of different variables with SVR. After adjustment for the influence of the confounding variables by logistic regression analysis, age < 50 (OR:7.0; 95% CI: 1.1 to 21.1), genotype 1a (OR: 1.8; 95% CI: 1.4 to 4.1), HCV-RNA < 5.6 log10 IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9), a fibrosis score ≤ S3 (OR: 3.8; 95% CI:3.2 to 7.4;), and ALT value < 100 IU/ml (OR:2.1 95% CI: 1.3 to 3.5) were all independent predictors of SVR while sex, and BMI were not associated with SVR.
                                                Table 3

                                                Factors associated with the likelihood of SVR. Crude and adjusted Odds Ratios (O.R.) derived by multiple logistic regression analysis

                                                 

                                                Crude O.R. (95% CI)

                                                Adjusted O.R.

                                                (C.I. 95%)

                                                HCV-RNA ≤ 5.6 log10 IU/ml

                                                2.9 (1.8-5.1)

                                                3.2

                                                (2.7-6.9)

                                                ≤ S3*

                                                3.8 (2.0-7.3)

                                                3.8

                                                (3.2-7.4)

                                                Subtype 1a

                                                1.9 (1.2-2.9)

                                                1.8

                                                (1.4-4.1)

                                                Age

                                                7.4 (0.9-40.0)

                                                7.0

                                                (1.1-21.2)

                                                < 50

                                                   

                                                > 50

                                                   

                                                BMI

                                                1.7 (1.0-2.8)

                                                1.4

                                                (0.8-2.5)

                                                < 25

                                                   

                                                > 25

                                                   

                                                ALT

                                                1.9 (1.2-3.0)

                                                2.1

                                                (1.3-3.5)

                                                < 100

                                                   

                                                > 100

                                                   

                                                Sex

                                                1.1 (0.7-1.7)

                                                1.3

                                                (0.8-2.2)

                                                RVR

                                                21.0 (11.5-38.3)

                                                3.2

                                                (1.3-7.7)

                                                Legend O:R: odds ratio; BMI: body mass index, ALT: alanine aminotransferase value IU/ml RVR rapid virological response.

                                                *322over 388 patients were submitted to liver biopsy and analyzed for this variable.

                                                Cross-tabulation of RVR vs.SVR showed that the positive predictive value (PPV) of RVR for the achievement of SVR was 82.0% for subtype 1a and 77.4% for subtype 1b (data not shown).

                                                Safety profile

                                                Eighteen subtype 1a (11%) and 16 subtype 1b (7%) patients stopped antiviral treatment due to adverse effects. Six patients stopped during the first month of treatment and the remaining patients during the following months. The percentage of patients in both groups whose treatment dose were decreased due to adverse events were comparable: 9.6% (16 patients) for subtype 1a and 10.7% (24 patients) for subtype 1b. Anaemia was the most frequent cause of dose reduction. Total discontinuation, dose modifications and adverse events related to treatment are showed in Table  4.
                                                Table 4

                                                Total discontinuation, dose modification and adverse events related to antiviral treatment

                                                 

                                                Subtype 1a n = 165

                                                Subtype 1b n = 223

                                                Total discontinuation n (%)

                                                18 (11)

                                                16 (7.1)

                                                -depression

                                                7 (4.2)

                                                3 (1.3)

                                                -fatigue

                                                10 (6)

                                                9 (4)

                                                -hyperthiroidism

                                                0

                                                1 (0.4)

                                                -anemia

                                                1 (0.6)

                                                3 (1.3)

                                                Adverse events n (%)

                                                7 (4.2)

                                                12 (5.3)

                                                -depression

                                                1 (0.6)

                                                3 (1.3)

                                                -hypothiroidism

                                                1 (0.6)

                                                0

                                                -anemia

                                                5 (3.0)

                                                7 (3.1)

                                                -neutropenia

                                                0

                                                2 (0.9)

                                                Dose modification n (%)

                                                16 (9.6)

                                                24 (10.7)

                                                Peginterferon

                                                9 (5.4)

                                                11 (5)

                                                Ribavirin

                                                7 (4.2)

                                                13 (5.8)

                                                n:number.

                                                Discussion

                                                We have conducted a large observational study to assess the influence of viral subtype within HCV genotype 1 on the virological response to antiviral treatment in naïve HCV patients. Logistic regression analysis showed that HCV subtype 1a, mild liver fibrosis scored as less than S3 (Ishak score), HCV-RNA level less than 5.6 log10 IU/ml, age less than 50 years, and ALT level less than 100 IU/ml were all independent predictors of SVR.

                                                Many efforts have been made to identify predictors of SVR to antiviral treatment in the difficult-to- treat chronic hepatitis C genotype 1 patients. Liver histology and viral HCV-RNA levels seem to be particularly important predictor of response in these patients. A recent study by Cheng et al. showed that naïve genotype-1 patients with advanced fibrosis were less likely to achieve SVR than those without advanced fibrosis [5]. Bruno et al. demonstrated that age and liver fibrosis predicted the response rate to PEG-INF and ribavirin combination therapy [6]. Few studies have investigated the impact of viral subtype on SVR genotype 1 patients. A study by Legrand-Abravanel et al. showed by multivariate analysis that genotype 1 subtype 1a was associated with a lower response to HCV therapy than subtype 1b [8]. However, this was an observational study with some potential confunding factors: more than 23% of the patients were concomitantly infected with HIV or HBV; and nearly 35% were interferon experienced patients. Similarly, Nicot et al. found that genotype 1b and HCVRNA < 15IU/ml were the only independent predictors of SVR in genotype 1 patients. However the population of patients analysed in this study was not homogeneous: 23% of all patients were coinfected with HIV and 42% had not responded to previous interferon treatment [9]. Zein et al. found no difference in SVR rates between subtype 1a and 1b patients treated with standard interferon [13]. The PROBE study, which included more than 6000 HCV infected patients, showed that SVR was marginally associated with subtype 1a ( OR 1.41; 95% CI 1.0-2.03) [7]. A recent observational study with a retrospective and prospective phase conducted in Italy (AIFA study), which included naïve, relapser and no responder patients, showed that genotype 1a naive patients experienced a rate of SVR around 6% higher than that observed for genotype 1b naïve patients and comparable to that observed in genotype 4 (retrospective phase-SVR G1a versus G1b 37.1 vs 31.6% p < 0.001 and prospective phase-SVR 31.0 vs 26.5% p < 0.001) [10]. A higher rate of adverse events and in particular of anemia reported in AIFA study, could have influenced the different rate of SVR observed respect to our study. We hypothesize that, in particular, an high rate of anemia could have been responsible for ribavirin or peginterferon dose modification in the AIFA study (data not reported).

                                                Genotype 1 subtypes 1a and 1b are the most common HCV genotypes in the United State. These subtypes are also predominant in Europe and subtype 1b is responsible for up to 73% of HCV infection in Japan. Zein et al. found that patients with HCV subtype 1b were older on average than those infected with other genotypes and that subtype 1b may have been present in some countries before the other genotypes. All patients who acquired HCV before 1955 were infected with subtype 1b. Subtype 1a was introduced in the late 1950s and then, it became the most prevalent genotype [13]. According to this model HCV subtype 1b is associated with more severe liver disease not because it is a more aggressive form of HCV but because it reflect a longer duration of infection [14]. In our study more genotype 1b than genotype 1a patients relapsed after treatment although the difference was not statistically significance. This difference could have been due to the higher percentage of slow responding patients in genotype 1b group than in genotype 1a group. Some studies have demonstrated a significant association between slow response and relapse in patients with an EVR [15, 16]. Although genotype 1a present a lower age and lower baseline HCVRNA level respect to genotype 1b patients, the logistic regression analysis and in particular Adjusted odds ratio shows the independent influence of genotype 1a on SVR without the disturbing influence of other variables. For the above- mentioned reasons subtype 1b patients may respond less favourably than subtype 1a patients to PEG-INF plus ribavirin.

                                                While we observed in dual antiviral therapy a better SVR of genotype 1a respect to genotype 1b patients, genotype 1a presents higher virologic failure respect to genotype 1b in patients treated with triple antiviral combination therapy including protease inhibitors Boceprevir or Telaprevir. Overall, the barrier to resistance is lower in genotype 1a than in genotype 1b strains, resulting in higher breakthrough rates in the former [17].

                                                In our study we found similar SVR in patients treated with pegylated interferon alfa-2a and alfa 2-b, this is in agreement with Ideal and AIFA study [10, 18] but it is in contrast with two italian randomized controlled studies that demonstrated higher SVR in genotype 1 patients treated with pegylated interferon alfa-2a [19, 20]. At present the superiority of one regimen over the other in terms of treatment efficacy remains unknown. The performance of the two drugs has not been explored in patients stratified by treatment modifiers such as fibrosis stage, basal viral load, insulin resistance, age and it is unlikely that future effort will extend current knowledge as we enter in the era of protease and polymerase inhibitors [21].

                                                The interleukin-28B (IL28B) polymorphism has been reported to influence viral kinetics and SVR in genotype 1 patients [22]. We did not determine this parameter in the present study; its significance was not known at the time that the study was conducted. Therefore, we cannot exclude the possibility that our subtype 1a patients may have had a more favourable IL28B polymorphism profile than did the subtype 1b patients. IL28B polymorphism could be an additional parameter explaining the uniquely higher SVR rate for subtype 1a versus 1b observed in the Italian population.

                                                Finally, we would like to emphasise that this study was conducted in “real- world- patients”, thus providing a representative picture of HCV treatment.

                                                Conclusion

                                                While in triple antiviral combination therapy including protease inhibitors Boceprevir or Telaprevir genotype 1a presents higher virologic failure respect to genotype 1b patients, we observed in dual antiviral therapy a better SVR of genotype 1a respect to genotype 1b patients that is independent of other factors that may favour viral clearance.

                                                Declarations

                                                Authors’ Affiliations

                                                (1)
                                                Liver Unit Azienda Ospedaliera San Camillo Forlanini
                                                (2)
                                                Liver Unit Ospedale Sandro Pertini
                                                (3)
                                                Department of Infectious and Tropical Disease Policlinico Umberto I
                                                (4)
                                                Liver Unit Policlinico Casilino
                                                (5)
                                                Liver Unit Ospedale Villa Betania
                                                (6)
                                                Infectious Disease Ospedale di Belcolle strada Sammartinese
                                                (7)
                                                Liver Unit Campus Biomedico University
                                                (8)
                                                Infectious Disease Ospedale San Camillo de Lellis
                                                (9)
                                                Department of Infectious Disease Policlinico Umberto I
                                                (10)
                                                National Institute of Health
                                                (11)
                                                Department of Digestive and Liver Disease, Azienda Ospedaliera Sant’Andrea
                                                (12)
                                                Medicine of Migration National Institute for Migrant Health and Poverty
                                                (13)
                                                Department of Internal Medicine and liver unit, Ospedale Generale di Marino
                                                (14)
                                                Department of Medical Pathophysiology, University of Rome La Sapienza
                                                (15)
                                                Liver Unit ASL RM/A
                                                (16)
                                                Infectious and Parasitic Diseases

                                                References

                                                1. McHutchison JG, Everson GT, Gordon SC, et al.: PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009, 360:1827–1838.PubMedView Article
                                                2. Kwo PY, Lawitz EJ, McCone J, et al.: SPRINT-1 investigators. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010, 376:705–716.PubMedView Article
                                                3. Fried MW, Shiffman ML, Reddy K, et al.: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002, 347:975–982.PubMedView Article
                                                4. Hadziyannis SJ, Sette H Jr, Morgan TR, et al.: PEGASYS International Study Group. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004, 140:346–355.PubMed
                                                5. Cheng WS, Roberts SK, McCaughan G: Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing. J Hepatol 2010, 53:616–623.PubMedView Article
                                                6. Bruno S, Cammà C, Di Marco V, et al.: Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial. Hepatol 2004, 41:474–481.View Article
                                                7. Rizzetto M, Colombo M, Ascione A, et al.: Effectiveness of hepatitis C virus treatment in real life practice: a prospective observational multicenter study in Italy (PROBE). J Hepatol 2008,2(48):S311.View Article
                                                8. Legrand-Abravanel F, Colson P, Leguillou-Guillemette L, et al.: Influence of the HCV subtype on the virological response to pegylated interferon and ribavirin therapy. J MedVirol 2009, 81:2029–2035.
                                                9. Nicot F, Alric L, Barange K, et al.: Influence of genotype 1 subtypes on the virus response to Peg interferon alpha-2a plus ribavirin therapy. J Med Virol 2011, 83:437–444.PubMedView Article
                                                10. Rosina F, Tosti ME, Borghesio E, et al.: PEG-IFN for chronic hepatitis C in clinical practice: the prospective phase of the AIFA study. Dig Liv Dis 2012, 44S:s12.View Article
                                                11. Knodell RG, Ishak KG, Black WC, et al.: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981, 1:431–435.PubMedView Article
                                                12. Dienstag JL, McHutchinson J: American Gastroenterological association technical review on the management of hepatitis C. Gastroenterology 2006, 130:231–264.PubMedView Article
                                                13. Zein NN, Rakela EL, Krawitt KR, Reddy KR, Tominaga T, Persing DH: Hepatitis C virus genotypes in United States: epidemiology, pathogenicity, and response to interferon therapy. Ann Intern Med 1996, 125:634–639.PubMed
                                                14. Zein NN: Clinical significance of hepatitis C virus genotypes. ClinMicrobiol Rev 2000, 13:223–235.
                                                15. Nevens E, Van Vlierberghe H, D’Heygere E, et al.: BERNAR-1 Study Group. A randomized open label, multicenter studyevaluating the efficacy of peginterferon alfa 2a, in combination with ribavirin, in naïve and relapsed chronic hepatitis C patient. Acta Gastroenterol Belg 2010, 73:223–228.PubMed
                                                16. Yu JW, Wang GQ, Sun LJ, Li XG, Li SC: Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon alpha-2a and ribavirin. J GastroenterolHepatol 2007, 22:832–836.
                                                17. Sarrazin C, Zeuzem S: Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010, 138:447–462.PubMedView Article
                                                18. McHutchison JG, Lawitz EJ, Shiffman ML, et al.: Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009, 361:580–593.PubMedView Article
                                                19. Ascione A, De Luca M, Tartaglione MT, et al.: Peginterferon alfa-2a plus ribavirin is nore effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection. Gastroenterology 2010, 138:116–122.PubMedView Article
                                                20. Rumi MG, Aghemo A, Prati GM, et al.: Randomized study of peginterferon alfa2a plus ribavirin vs peginterferon alfa2b plus ribavirin in chronic hepatitis C. Gastroenterology 2010, 138:108–115.PubMedView Article
                                                21. Rumi MG, Aghemo A, Prati GM: Comparative trials of peginterferon alfa-2a and peginterferon alfa-2b for chronic hepatitis C. J Viral Hepatol 2012, 19:37–41.View Article
                                                22. Thompson AJ, Muir AJ, Sulkowski MS, et al.: Interleukin-28B polymorphism improves viral kinetics and is the strongestpretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010,2010(139):120–129.View Article
                                                23. Pre-publication history

                                                  1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-230X/​12/​162/​prepub

                                                Copyright

                                                © Pellicelli et al.; licensee BioMed Central Ltd. 2012

                                                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.