Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C
Abstract
Genotype 2 (HCV-2) accounts for 8% of the patients with chronic hepatitis C virus in Europe. Because of the favourable response to interferon (IFN)-based treatment, this group is considered an ‘easy-to-treat’ genotype along with HCV-3. However, experimental and clinical data suggest possible differences between HCV-2 and -3. Recently, subtle differences in treatment efficacy have also been shown in response-guided treatment studies. In these studies, the duration of pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment was tailored according to treatment response. Although SVR rates were similar between HCV-2 and HCV-3 patients after a rapid virological response (RVR), in the absence of RVR, the rates were lower in HCV-3 than in HCV-2. The triple combination treatment, including direct-acting antivirals (DAA) that will be commercialized in the coming months might increase SVR rates in this particular subgroup of patients. According to existing results, telaprevir might be beneficial in HCV-2 but not in HCV-3 patients. A nucleotide analogue polymerase inhibitor, PSI-7977 by Pharmasett has been shown to be active against both. The role of the IL28B polymorphism as a predictor of response to the current standard of care (SoC), PEG-IFN and RBV treatment is the subject of debate, but this mainly seems to be because of the small size of the samples in the studies performed so far. Existing results suggest that the genetic evaluation of IL28B may be useful in patients with HCV-2 for predicting response in patients without RVR.
Epidemiological background
Epidemiological background
In the European countries, the most frequent HCV genotype is genotype 1 followed by genotypes 3, then 2 (Table 1). Despite these epidemiological differences, HCV-2 and -3 are usually analysed together on the basis of similar favourable responses to IFN treatment. Studies exploring a reduction in treatment duration have recently highlighted potential differences between these two genotypes. A mean prevalence of 8.2% has been reported in Europe for genotype 2, ranging from a prevalence of 0.9% in Turkey to 27% in Italy [1]. In 1997, genotype 2 was observed in 38% of the HCV chronic infected patients referred to our centre [2]. Although the corresponding prevalence of genotype 3 in that study was less than 5%, a wave of genotype 3 infection is currently also increasing the proportion of HCV-3 infected patients in Italy [3]. The HCV-2 is observed in 3% and 9% of HCV patients, in Spain and in France respectively. Outside of Europe, a high frequency of HCV-2 has been reported in some Southern African and Asian areas where it accounts for 30% of chronic HCV infection overall [4].
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Table 1. Hepatitis C virus genotypes frequency by country
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Table 1. Hepatitis C virus genotypes frequency by country
HCV genotype 2 treatment: PEG-IFN and ribavirin combination
These results are supported by those of a recent meta-analysis evaluating six trials of standard or shortened treatment. Sensitivity analysis by genotype showed that an SVR was achieved by 84% of HCV-2 rapid responders with no significant differences between standard or shortened duration when weight-based dosages of RBV were used for 16 weeks. The corresponding rate in patients with HCV-3 was 81%, but the difference between short and standard duration was greater perhaps because of the use of fixed doses of RBV [22].
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Table 3. Rates of non-RVR and SVR in patients with HCV-2 and HCV-3 who received 24 weeks of treatment
Table 4. Rates of IL28B SNP distribution and SVR by on-treatment response and IL28B
The combination of PEG-IFN and RBV has been shown to be very successful in patients with genotype 2. The AASLD guidelines [5] advise treating HCV-2 and -3 patients for 24 weeks with combination treatment, including PEG-IFN alpha-2a or alpha-2b and a fixed dose of 800 mg of RBV [6]. With this treatment, more than 80% achieve SVR. However, because experimental and clinical data suggest possible differences between HCV-2 and -3 [7, 8, 9], it may be worthwhile to focus on response rates by genotype for the future scenario of the treatment of hepatitis C.
One trial by Zeuzem and the large ‘real-world’ WIN-R study reported a 9% difference between HCV-2 and -3 genotypes in SVR rates in favour of HCV-2 after 24 weeks of treatment [10, 11]. Recently, REDD 2/3 another ‘real-world’ study analysed HCV-2 and -3 separately in an evaluation of both a lower dose of PEG-IFN alpha-2b and a reduced duration of treatment [12]. This study reported somewhat higher rates of relapse in patients with HCV-3 than in those with HCV-2 after 24 weeks of PEG-IFN alpha-2b and weight-based RBV [12].
To reduce the costs and spare the side effects of combination treatment, several studies have investigated the effectiveness of treatment for less than 24 weeks after an RVR. Several studies in Europe and one study from Taiwan [13] have shown that a course of treatment with PEG-IFN and weight-based RBV for 12–16 weeks was not less effective or was cost-effective compared to the standard of 24 weeks [13, 14, 15, 16, 17]. However, one larger multicenter study, using a fixed dosage of RBV did not demonstrate that the two treatments were not less effective [18]. Based on the analysis of results in the literature, the updated European guidelines conclude that HCV-2 and -3 can be treated for 12–16 weeks when HCV RNA is undetectable after 4 weeks of treatment, as long as there is no advanced liver disease or obesity and RBV is weight-based [19]. The guidelines suggest that a short course of treatment may be slightly less effective in patients with HCV-3.
In a meta-analysis evaluating customized treatment of patients with HCV-2 and -3 in four studies, including 957 patients for whom separate data are available for both genotypes, we showed that SVR rates in HCV-3 patients with RVR were similar to those of HCV-2 patients [20]. The difference between the two genotypes is the probability of SVR in patients without RVR. In the absence of RVR [20], EASL guidelines advise 24 or 48 weeks of treatment depending on whether the patient is HCV RNA-negative or if there is a greater than 2 log10 decline in HCV RNA at week 12 respectively. However, the recommended schedule for HCV-2 and HCV-3 patients is the same [19].
Rapid virological response, SVR and relapse rates for HCV-2 patients in studies on short treatment duration with separate analysis of HCV-2 and -3 are shown in Table 2. Patients with HCV-2 infection had extremely high RVR rates ranging from 68 to 87%. No significant differences were observed in the SVR rate after 12 or 24 weeks of treatment once RVR was achieved (Table 2). After 24 weeks of treatment, the risk of relapse in patients with HCV-2 is low and the increased risk as a result of a short treatment course appears to be clinically irrelevant. Indeed, only the Accelerate study reported relapse rates increase of more than 12% in the short treatment arm when compared with the standard duration. The analysis by Diago [21] took into account only the subgroup of patients with RVR. This result may be explained by a high proportion of patients with advanced liver disease were enrolled in the short treatment arm; 28% of patients who received 16 weeks of PEG-IFN plus fixed 800 mg doses of RBV had bridging fibrosis or cirrhosis [18].
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Table 2. Response rates in HCV-2 patients enrolled in studies on short or standard treatment duration
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Table 2. Response rates in HCV-2 patients enrolled in studies on short or standard treatment duration
These results are supported by those of a recent meta-analysis evaluating six trials of standard or shortened treatment. Sensitivity analysis by genotype showed that an SVR was achieved by 84% of HCV-2 rapid responders with no significant differences between standard or shortened duration when weight-based dosages of RBV were used for 16 weeks. The corresponding rate in patients with HCV-3 was 81%, but the difference between short and standard duration was greater perhaps because of the use of fixed doses of RBV [22].
Table 3 reports the SVR rates in patients without RVR by genotype, in studies with data on 24 weeks of treatment. Unlike in HCV-3 patients, the SVR in HCV-2 patients who do not achieve RVR is above 60%. Increasing the SVR rate in patients without RVR is still an unresolved issue.
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Table 3. Rates of non-RVR and SVR in patients with HCV-2 and HCV-3 who received 24 weeks of treatment
Table 4. Rates of IL28B SNP distribution and SVR by on-treatment response and IL28B
Future therapies
Recently approved DAA inhibitors of HCV replication are expected to provide a major step forward in the treatment of HCV infection. Several small molecules, mainly inhibitors of HCV NS3/4A protease and NS5B polymerase are in the process of being commercialized in Europe.
Although DAA will improve virological response rates in patients with genotype 1, the development of small molecules effective against HCV genotypes other than one is in earlier stages [23]. Telaprevir, the first agent to directly target viral replication, has been shown to be active against HCV-2, but not against HCV-3. Telaprevir is a powerful oral protease inhibitor [24, 25] that can increase the SVR in genotype 1 HCV by about 30% compared to standard PEG-IFN/RBV. The activity of telaprevir was investigated in patients with HCV-2 and HCV-3 in the C209 study. The combination of telaprevir plus PEG-FN alpha-2a and RBV was evaluated in five patients with HCV-2 and compared to telaprevir alone in nine patients and to PEG-IFN and RBV in an additional nine patients in the control group. The triple combination therapy resulted in SVR rates of 100% which is remarkable considering the 89% rate observed in patients receiving standard PEG-IFN/RBV [26]. Conversely, telaprevir monotherapy had little or no activity in patients infected with HCV-3. In that study, telaprevir was administered as monotherapy or in combination with PEG-IFN for only 2 weeks, while the overall duration of treatment was 24 weeks in each arm. It should be noted that the histological diagnosis of cirrhosis was an exclusion criteria in this study.
Other NS3/4A protease inhibitors, nucleoside and non-nucleoside reverse replicase inhibitors as well as NS5A inhibitors have shown to have antiviral activity against HCV-2. One of the most promising drugs so far is PSI-7977, a nucleotide analogue polymerase inhibitor [27]. In the Proton study, an open label study, the drug was evaluated in 15 patients infected with HCV-2 and in 10 infected with HCV-3 as well as in a larger group of patients with HCV-1 infection [28]. That study, whose results were presented at the last EASL meeting, reported an RVR of 96% after the triple combination of 400 mg of PSI-7977 plus PEG-IFN/RBV. Twenty-four HCV-2 and -3 patients who completed the 12 weeks of treatment achieved SVR (96%). Patients with cirrhosis were excluded. The Electron study, an ongoing study, is currently evaluating this triple combination in an IFN sparing regimen strategy of only 8 weeks of triple combination treatment.
The role of IL28B to modify treatment strategies
The role of IL28B to modify treatment strategies
The recent identification of a single nucleotide polymorphism (SNP) upstream from the IL28B gene associated with a response to IFN-based treatment is a landmark observation [29, 30, 31]. Genotype 1 patients with IL28B CC genotype had higher response rates compared to those with the rs12979860 TT alleles. Previous data proposed that interferon stimulated genes (ISGs) are up-regulated in non-responders prior to treatment [32, 33]. Genetic variation of the IL28B gene may explain the pre-activation of interferon stimulated genes (ISGs) in non-responder patients to IFN-based treatment, because the subjects with the unfavourable IL28B TT genotype have higher levels of activation of ISGs in the liver [34].
Distribution of CC genotypes in patients with HCV genotype 2
Distribution of CC genotypes in patients with HCV genotype 2
Numerous studies have investigated IL28B in patients with HCV-2 and -3 analysing both genotypes together. Separate analyses of the frequency of IL28B in patients with HCV-2 and -3 infections have only been performed in two studies, one by Sarrazin, and other by ours [35, 36] (Table 4). In both cases, the rs12979860 SNP was investigated [35].
Sarrazin et al. evaluated 378 patients with HCV-1, 77 with HCV-2 and 190 with HCV-3 [35]. They showed that the frequency of the CC genotype in patients with genotype 1 was 33.9%, whereas in patients with HCV-2 and HCV-3, it was 42.7%. When HCV-2 and -3 were analysed separately, the CC genotype was observed in 51.9% of those with HCV-2 compared to 38.9% of patients with HCV-3. When these frequencies were compared to those in the general population (49%), the difference between patients with HCV genotype 1 and healthy controls was high and statistically significant (P < 0.001). The difference in frequency between HCV-2 and the normal population was not statistically significant (P = 0.116). The frequency of the CC genotype in HCV-1 was significantly lower than that in HCV-2 patients (P = 0.045). No difference was observed in the frequency of CC between HCV-1 and -3 patients (P = 0.43).
Our group performed a study on the IL28B polymorphism in a cohort of 268 patients with HCV-2 (n = 215) (Table 4) and HCV-3 (n = 55) who were previously randomized in a multicenter-controlled trial to a treatment of variable or standard duration [36]. The favourable IL28B CC genotype was present in 37% of patients. When this group was compared to a cohort of HCV-1 patients in the same geographical area, the frequency of the CC genotype was slightly higher (37% vs 29% respectively). In the general population, the IL28B CC genotype was detected in 42% of cases. As in the study by Sarrazin, we observed a lower frequency of the CC genotype in patients with HCV-1 compared to the general population, but the difference was not significant. Differences between HCV-2 and control patients were not identified.
It is unclear if these variations in distribution are an effect of the functional mechanisms that lead to the development of chronic HCV infection, as previously suggested [37]. A prospective study in a large cohort of patients, including different HCV genotypes and subtypes in the presence of a specific IL28 genotype is required to clarify this issue.
SVR response in patients with HCV genotype 2 by IL28B
SVR response in patients with HCV genotype 2 by IL28B
Several independent genome-wide association studies (GWAS) reported SNPs near the IL28B (IFN-λ3) locus that displayed association with treatment response, mainly in genotype 1 infected patients. Furthermore, in a mono-centric cohort of genotype 4 infected patients from three different ethnic groups (Egyptian, European and Sub-Saharan African), IL28Brs12979860 CC genotype was associated with a higher sustained virological response [38].
In contrast, available data on the predictive role of the IL28B polymorphism on SVR are conflicting for patients with HCV-2 and -3 infections. Some studies have failed to demonstrate any clear association between the IL28B polymorphism and SVR in patients with HCV-2 or -3 infection [39, 40]. Others have reported a positive association between the favourable rs12979860 CC or rs8099917 TT genotype, respectively, with RVR, but not SVR [41], suggesting an increased rate of relapse in this subset of patients. Finally, two European studies, including ours, examining HCV-2 and HCV-3 together, have shown that CC is associated with SVR [35, 36].
In our study, the association was largely driven by the subgroup of patients who did not achieve RVR [36]. Indeed, we observed that the IL28B CC genotype selects those who will respond to treatment among non-RVR patients. In contrast, the SVR rates in patients without RVR and with the TT genotype were negligible.
The CC genotype was not associated with RVR in the standard treatment arm or in patients who achieved RVR and were therefore treated for only 12 months. This lack of association may be a consequence of the rate of RVR observed in the different series of HCV-2 patients studied so far; larger numbers of patients would probably equalize the different results. In our cohort, CC genotype was an independent baseline predictor of SVR.
Our results suggest that IL28B may play a role in some patients, particularly those who do not achieve RVR, as defined by undetectable HCV RNA in serum after 4 weeks of treatment with an assay of sensitivity ≤ 50 IU/ml.
No association was found between RVR and IL28B genotype in the study by Sarrazin et al. evaluating 58 patients with HCV-2 and 147 with HCV-3 infection treated with PEG or standard IFN [35]. However the authors found an overall association with SVR, and with SVR in RVR patients, in particular. The main limitation of this study was the heterogeneity of previous treatment regimens, including IFN monotherapy. This may explain why the association with SVR was not statistically significant.
One difference between American patients and the HCV-2 patients evaluated in Sarrazin's and our study was that an intermediate degree of IFN sensitivity was observed in patients with the CT genotype.
Conclusions
Conclusions
Patients infected with genotype 2 HCV are an ‘easy-to-treat’ population. As a result of the very high successful response rate and the possibility of shortening the duration of treatment in nearly all patients who achieve an RVR in the absence of cirrhosis, treatment of HCV-2 with a standard combination of PEG-IFN/RBV may be continued.
The DAA potentially active against HCV-2 should be explored to increase the SVR response rates in the subgroup of patients without RVR whose SVR rates remain unsatisfactory, with the combination of PEG-IFN/RBV. In patients without RVR, IL28B might be a useful predictor of SVR after PEG-IFN/RBV combination treatment.
Conflicts of interest
Conflicts of interest
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