Which patients with genotype 1 chronic hepatitis C can benefit from prolonged treatment with the accordion regimen? q

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1 Journal of Hepatology 47 (2007) Special article Which patients with genotype 1 chronic hepatitis C can benefit from prolonged treatment with the accordion regimen? q Patrick Marcellin 1, *, E. Jenny Heathcote 2, Antonio Craxì 3 1 Service d Hépatologie and INSERM CRB3, University Paris 7, Hôpital Beaujon, Clichy, France 2 University of Toronto, Toronto, Ont., Canada 3 Liver & GI Unit, Di.Bi.M.I.S., University of Palermo, Italy The on-treatment virological response to pegylated interferon plus ribavirin therapy is a useful tool in the management of patients with chronic hepatitis C. The time at which hepatitis C virus RNA becomes undetectable by a sensitive PCR assay has a huge impact on the probability of achieving a sustained virological response, particularly in genotype 1 patients, and may be useful in selecting patients for prolonged therapy. Indiscriminate extension of treatment in patients with hepatitis C virus genotype 1 is not beneficial. However, there is a subgroup of patients the so-called slow responders who benefit from extending treatment from 48 to 72 weeks and can be readily identified after 4 12 weeks of combination therapy. Thus, it is important to distinguish slow responders from null responders. In the TeraVIC-4 study virological relapse rates were significantly lower, and sustained virological response rates were significantly higher, in those treated for 72 weeks with peginterferon alfa-2a (40 kda) plus ribavirin (45% vs. 32% with 48 weeks, P = 0.014). Patients are best served by quantitative determination of the hepatitis C virus RNA level at weeks 4, 12 and 24. The results of these determinations can then be used to tailor the length of therapy. Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Chronic hepatitis C; Combination therapy; Extended treatment; Peginterferon; Pegylated interferon; Ribavirin; Prolonged therapy; Rapid virological response; Viral kinetics 1. Introduction Associate Editor: J.G. McHutchison q Prof. Patrick Marcellin declared that he is an investigator, advisor and speaker for both Roche and Schering Plough. In addition he declared he received no funding from the manufacturers or from any source to carry out this study. * Corresponding author. Address: Service d Hepatologie, Inserm U773, 100 Bd du General Leclerc, Clichy, France. Tel.: ; fax: address: patrick.marcellin@aphp.fr (P. Marcellin). The development of sensitive and specific assays for hepatitis C virus (HCV) RNA has allowed clinicians to study viral kinetics, and to focus on viral eradication as a treatment endpoint rather than alanine aminotransferase normalisation, which is an imperfect surrogate for efficacy. Perhaps the most important discovery regarding the biology of HCV has been the identification of a number of discrete HCV genotypes, and the recognition of the marked influence that genotype has on the response to interferon-based treatment. Overall sustained virological response (SVR) rates have ranged from 54% to 63% in phase III trials [1 3] SVR rates are consistently lower in patients infected with HCV genotype 1 or 4 than in those with genotype 2 or 3. A high baseline HCV RNA level has a negative influence on outcomes in patients infected with HCV genotype 1, 3 or 4 [1 3], but possibly not genotype 2 [4] This phenomenon is illustrated in SVR rates obtained with combination therapy in a phase III study (Fig. 1) [2]. The results of large pivotal trials are the basis on which treatment guidelines have been established. The currently recommended regimen for genotype 1 patients is a fixed 48-week combination regimen comprising a /$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 P. Marcellin et al. / Journal of Hepatology 47 (2007) Sustained virological response (%) All genotype 1 patients (n=271) pegylated interferon plus ribavirin [5 7]. These individuals must be treated with the standard dose of ribavirin (1000 or 1200 mg/day) in order to maximise the probability of SVR. Viral load is not currently used to guide treatment, although patients with low serum HCV RNA levels are more responsive to treatment. Different definitions for low serum HCV RNA level (i.e., <800,000 IU/mL vs. <600,000 IU/mL) have been used in clinical trials, but the best cut-off for identifying those most likely to respond is <400,000 IU/mL [8]. Patients with high HCV RNA levels at the start of treatment may not achieve an early virological response (EVR) at week 12 and may take longer to achieve negative serum HCV RNA under treatment [9]. Much effort has been devoted to improving treatment outcomes in patients infected with HCV genotype 1, most of whom have high viral loads. The use of higher drug doses in obese patients is one strategy that is under active investigation [10]. Prolonging the duration of treatment is another strategy that has shown promise. Prolonged treatment has the potential to improve cure rates, although it will increase the cost of treatment and may increase the probability that a patient will experience adverse events. For these reasons careful patient selection with the aid of viral kinetics is important. 2. Viral kinetics and patient management: the accordion effect The on-treatment virological response to combination therapy is a useful tool in patient management. The time at which HCV RNA becomes undetectable by a sensitive PCR assay has a huge impact on the probability of SVR. Genotype 1 patients who had 65 Patients with low baseline HCV RNA level (n=85) 47 Patients with high baseline HCV RNA level (n=186) Fig. 1. Sustained virological response rates in treatment-naïve genotype 1 patients receiving 48 weeks of therapy with peginterferon alfa-2a (40 kda) plus ribavirin 1000 or 1200 mg/day in a large, randomised, multicentre study [2]. A low HCV RNA level was defined as 6800,000 IU/mL. undetectable HCV RNA or a P2-log 10 decrease in HCV RNA after 12 weeks of treatment had a 58% probability of achieving SVR after 48 weeks of treatment with peginterferon alfa-2a (40 kda) plus ribavirin in a randomised phase III trial (Table 1) [9]. In contrast, very few patients who did not meet this criterion referred to as an EVR achieved SVR (negative predictive value = 98%) [9]. Other analyses [11] have confirmed these findings and, as a result, a 12-week decision criterion has been incorporated into treatment guidelines [5 7] The application of this criterion is intended to identify patients most likely to achieve SVR with the standard duration of treatment (48 weeks). Patients who do not achieve an EVR have a very low (<3%) probability of SVR when treated with the conventional 48-week schedule of combination therapy; hence all international guidelines currently recommend discontinuation of treatment in these individuals. The development and application of the 12-week stopping rule has been an important development. However, strict application of this rule might deny the potential benefits of therapy to a significant number of patients if, for example, modification of the treatment regimen could increase the likelihood of SVR. In contrast to the all or none approach implied by the 12-week rule, a more nuanced approach to patient management based on viral kinetics might increase overall cure rates by allowing clinicians to customise the duration of therapy. Some genotype 1 patients achieve optimal outcomes with a shorter than customary duration of therapy [12,13]. A subset of patients with a rapid virological response (RVR), defined as undetectable HCV RNA (<50 IU/mL) at week 4 of treatment, achieved a very high SVR rate after just 24 weeks of treatment with peginterferon alfa-2a (40 kda) plus ribavirin [12] Among patients randomised to 24 weeks of treatment, the SVR rate was 89% in those with a RVR and approximately 20% in those without a RVR [12]. A total of 24% of patients randomised to 24 weeks of therapy had a RVR. Of note, patients with a baseline HCV RNA level 6600,000 IU/mL were significantly more likely to achieve a RVR than those with a baseline HCV RNA level >600,000 IU/mL (38% vs. 9%). The Table 1 Relationship between time by which a genotype 1 patient becomes HCV RNA negative (<50 IU/mL) and sustained virological response [9] Treatment week Patients who became HCV RNA-negative for the first time, n (%) SVR (%) 4 33 (13) (43) (20) 45 Data are from 260 genotype 1 patients treated with peginterferon alfa- 2a plus ribavirin 1000 or 1200 mg/day in a randomised, international phase III trial.

3 582 P. Marcellin et al. / Journal of Hepatology 47 (2007) Decrease in HCV RNA (log 10 copies/ml) 0 >0.5 >2.0 Rapid virological response Treatment start Pretreatment Null response Flat partial response Week 4 6 Slow partial response Week 12 SVR Treatment end Relapse Follow-up Limit of detection by PCR Fig. 2. Range of possible virological responses in patients with chronic hepatitis C treated with the combination of pegylated interferon plus ribavirin. Treatment started 1 st time HCV RNA negative Duration of treatment Fig. 3. The accordion effect. The time required for HCV RNA clearance affects the overall duration of therapy needed to obtain SVR. Based on data from several prospective studies [4,13,18,19,39,40]. results of a prospective noncomparative study are similarly compelling [13]. In contrast to the excellent prognosis of patients with a RVR, a substantial subgroup of patients does not achieve SVR after the recommended treatment duration of 48 weeks. A longer than customary duration of treatment may improve outcomes in these individuals. The key to customising treatment duration for both the super responders and the slow responders is the viral kinetic response during the early phase of treatment. The DITTO study was the first large trial that attempted to customise treatment regimens on the basis of viral kinetics [14]. Slow partial responders were defined in a very precise manner: the absence of a RVR at week 4, a second-phase decline in serum HCV RNA P0.09-log/day, and either a P1-log decrease in HCV RNA during the first 4 weeks of treatment or a first-phase decrease in HCV RNA of P0.5-log and an absolute decrease in HCV RNA at week 4 of P0.6- log. This ensured that patients with the possibility of complete viral suppression were included and that null responders and flat responders those unlikely to achieve virological suppression were excluded (Fig. 2). Among genotype 1 patients with a slow partial response, the SVR rate was 50% in those who were assigned to 72 weeks of treatment with peginterferon alfa-2a (40 kda) plus ribavirin, and 43% in those who received 48 weeks of combination therapy. All patients received peginterferon alfa-2a (40 kda) monotherapy during the first 6 weeks of the DITTO trial, which is not consistent with current guidelines, and the groups were too small to draw meaningful conclusions. For these reasons, the results of DITTO have not changed clinical practice. A retrospective analysis of data from a large randomised trial suggests that the duration of treatment after a patient becomes HCV RNA negative may be a determinant of SVR [15]. The authors tested the hypothesis that the probability of achieving SVR increased with the duration of time that HCV RNA was suppressed below the limit of detection during treatment. The mathematical model developed in this analysis predicts that the probability of SVR is 80% and 90% if combination therapy is continued for 32 or 36 weeks, respectively, after HCV RNA becomes undetectable in genotype 1 patients [15]. This suggests that treatment must be continued for a minimum period of time after HCV RNA levels have been suppressed below the limit of detection (<50 IU/ ml) in order to maximise the probability of achieving SVR [15]. The obvious conclusion to draw from this study is that the subset of patients who do not achieve an EVR require prolonged treatment to achieve SVR. Therefore available data suggest that, across all HCV genotypes, a sort of accordion effect exists: the earlier HCV RNA is cleared after the initiation of treatment, the shorter the duration of treatment to achieve SVR (Fig. 3). This implies that the future of treatment for patients harbouring interferon-sensitive HCV strains will involve optimisation of treatment according to viral kinetics. 3. Prolonging the duration of treatment: what proof of benefit? Extending treatment with combination therapy to a fixed duration of 72 weeks increases SVR rates in a subset of patients infected by HCV genotype 1. The concept of extended treatment was first explored in small studies [16,17], but data are now available from large randomised clinical trials [18,19]. It must be acknowledged, however, that all trials to date have used a ribavirin regimen that is considered suboptimal in all but those weighing less than 75 kg. In the first randomised trial to evaluate extended therapy, the rate of virological relapse during follow-

4 P. Marcellin et al. / Journal of Hepatology 47 (2007) up was significantly reduced from 38% to 13% by increasing the duration of treatment with conventional interferon plus ribavirin from 24 to 72 weeks [17]. In this study, extended treatment reduced relapse rates in difficult-to-cure subgroups, such as patients with genotype 1 infection or a high baseline HCV RNA level, and those with cirrhosis. Importantly, in late responders (patients with detectable HCV RNA at week 12), relapse rates dropped from 70% in individuals treated for 24 weeks to 30% in those treated for 72 weeks. These compelling data are mainly of historical interest because pegylated interferons have superseded conventional interferon [17]. Two recently published trials suggest that extended treatment may optimise SVR rates in some patients [18,19]. There are also preliminary reports from ongoing or recently completed trials of extended therapy [20 23], including some that were conducted in HIV HCV coinfected patients [24,25]. Before describing the results of two studies that suggest that extended therapy increases efficacy in some subgroups of patients with HCV monoinfection, it is important to state unequivocally that indiscriminate extension of treatment in patients with HCV genotype 1 is not beneficial. We know this because there was no overall benefit of treatment for 72 weeks versus 48 weeks in a large randomised trial (SVR rates by intention-to-treat analysis were 54% vs. 53%, respectively; Table 2) [18]. Despite the apparently discouraging results, careful analysis of the data was useful in identifying specific subgroups that benefited from extended treatment with peginterferon alfa-2a (40 kda) plus ribavirin. Patients who were HCV RNA detectable at week 12 had significantly improved SVR rates with prolonged treatment (29% vs. 17% with the standard treatment duration; P = 0.04). The cure rate of approximately 30% in these individuals is truly remarkable when one considers that a lower than recommended dosage of ribavirin for genotype 1 infection was used in the study (800 mg/day rather than 1000 or mg/day) [18]. Patients with a slow virological response (those who were HCV RNA detectable at week 4 or week 12, but HCV RNA negative at week 24) derived benefit from extended therapy. Prolonged treatment significantly reduced the rate of virological relapse in patients with detectable HCV RNA at weeks 4 or 12 (Fig. 4). The prolonged treatment strategy was most beneficial in patients with detectable but low HCV RNA levels (<6000 IU/ ml) at week 12. The virological relapse rate in these individuals was reduced from 57% in the 48-week treatment group to 32% in the 72-week treatment group. The most compelling data from the study by Berg et al. [18] were generated by retrospective analyses. The results of a prospective randomised study [19] confirm the hypothesis proposed by Berg et al. [18]. In the TeraVIC-4 study [19], only patients with detectable HCV RNA after 4 weeks of treatment with peginterferon alfa-2a (40 kda) plus ribavirin were eligible for randomisation to a total of 48 or 72 weeks of treatment. This ensured that only patients with a slow virological response were targeted for prolonged treatment (Table 2). Prolonged treatment significantly decreased the virological relapse rate (26% vs. 48% with 48 weeks, P = 0.003) and significantly increased the SVR rate (45% vs. 32% with 48 weeks, P = 0.014; Fig. 5). TeraVIC-4 has thus shown that prolonged treatment is beneficial in some, but by no means all, patients, and, most importantly, that a sensitive qualitative PCR test at week 4 can be used to identify those most likely to benefit. The virological response at week 12 was not determined in the study, but one can assume that the patients who benefited from prolonged treatment would have had a suboptimal HCV RNA response at week 12, as in the study by Berg et al. [18]. Limitations of Tera- VIC-4 include the use of a lower than recommended dose of ribavirin for genotype 1 (800 mg/day rather than 1000 or mg/day), inclusion of non-genotype 1 patients, and a high rate of voluntary withdrawal in patients randomised to prolonged treatment. The difference in treatment discontinuation rates was 17 18% higher in patients randomised to prolonged therapy as Table 2 Sustained virological response rates in treatment-naïve patients receiving peginterferon alfa-2a (40 kda) 180 lg/week plus ribavirin 800 mg/day for 48 or 72 weeks in large, randomised, multicentre studies Reference Duration of treatment Total no. of patients randomised Virological response rate (%) End of treatment Sustained virological response Berg et al. a [18] 48 weeks weeks Sánchez-Tapias et al. b [19] 48 weeks weeks * a Patients were randomised at baseline to either 48 or 72 weeks of treatment. b Patients were randomised on the basis of a week 4 PCR test. Only those with detectable HCV RNA (>50 IU/mL) were randomised to 48 or 72 weeks of treatment. * P < 0.05 vs. 48 weeks.

5 584 P. Marcellin et al. / Journal of Hepatology 47 (2007) Group A (48 weeks) Group B (72 weeks) P = Relapse rates (%) P = P = 0.2 P = /46 5/32 19/123 12/102 46/124 28/122 30/47 21/52 Patients with rapid virological response (HCV RNA < 50 IU/mL) at Week 4 Week 12 Patients with slow virological response (HCV RNA 50 IU/mL) at Week 4 Week 12 < but < 50 IU/mL at week 24 Fig. 4. Frequency of virological relapse rates in patients with rapid and slow virological responses at weeks 4 and 12. Patients in group A were treated for 48 weeks and patients in group B were treated for 72 weeks with peginterferon alfa-2a (40 kda) 180 lg/week plus ribavirin 800 mg/day in a large, randomised, multicentre study. compared with the standard duration in the two studies [18,19], which suggests that patients find it more difficult to adhere to the longer regimen. An ongoing study of extended therapy (SUCCESS) is using weight-based ribavirin [26]. A total of 17% of patients had a very slow virological response (<2-log decrease in HCV RNA) after 12 weeks of treatment with pegylated interferon alfa-2b (12KD) plus ribavirin mg/day [20]. Prolonged therapy is also being evaluated in previously treated patients in the ongoing REPEAT study [27 29]. Studies of prolonged treatment have demonstrated that exclusive use of the 12-week rule compromises the chance of SVR in some patients with poor prognostic characteristics. Patients are best served by quantitative determination of the HCV RNA level at weeks 4, 12 and 24. The optimal time at which to obtain blood samples for these tests is the day before the 5th, 13th Patients (%) weeks 72 weeks 32 P = SVR rate P = Relapse rate Fig. 5. Sustained virological response rates and virological relapse rates in patients randomised to 48 or 72 weeks of therapy with peginterferon alfa-2a (40 kda) plus ribavirin 800 mg/day. Only patients who were HCV RNA detectable (>50 IU/mL) at week 4 were randomised [19]. and 25th injections. The results of these determinations can then be used to tailor the length of therapy (Fig. 6). Future studies will determine whether more sensitive HCV RNA assays can improve our ability to predict which patients require longer durations of therapy. Not all slow responders are the same. There is a small subgroup of patients who remain HCV RNA positive after 24 weeks of treatment [9]. As yet, no strategy has been devised to improve the likelihood of SVR in these individuals. 4. Prolonged treatment: is the rate of success compromised by tolerability? When selecting patients for prolonged therapy, the importance of adherence to therapy must be stressed. Peginterferon + RBV 1000 or 1200 mg/day Quantitative PCR at baseline < 600,000 IU/mL >600,000 IU/mL Qualitative PCR at week 4 Treat for 24 weeks Treat for 48 weeks Treat for 48 weeks Quantitative PCR at week 12 > ( ) (+) ( ) 2-log drop Check at week 24 ( ) (+) Treat for 72 weeks <2-log drop Stop Fig. 6. Proposed algorithm for the selection of genotype 1 patients for extended treatment based on published data [12,18,19].

6 P. Marcellin et al. / Journal of Hepatology 47 (2007) The tolerability of prolonged therapy does not differ from that of the standard duration, but the number of voluntary withdrawals is greater in patients randomised to prolonged therapy [18,19]. In TeraVIC-4 [19], 24 patients (15%) randomised to prolonged therapy withdrew from treatment voluntarily, compared with 8 individuals (5%) randomised to the standard duration. The data from Berg et al. [18] are consistent with this finding: 16 (7%) and 4 (2%) patients randomised to the prolonged and standard durations of therapy, respectively, withdrew voluntarily. The incidence of serious adverse events in those randomised to the prolonged and standard durations of therapy was 11.1% and 15.6%, respectively, in the trial by Berg et al. [18] and 8% and 4.8%, respectively, in TeraVIC-4 [19]. The incidence of peginterferon alfa-2a (40 kda) dose reductions in those randomised to the prolonged and standard durations of therapy was 12% and 16%, respectively, in the trial by Berg et al. [18] and 30% and 25%, respectively, in TeraVIC-4 [19]. Similarly, the incidence of ribavirin dose reductions in those randomised to the prolonged and standard durations of therapy was 6% and 10%, respectively, in the trial by Berg et al. [18] and 29% and 20%, respectively, in Tera- VIC-4 [19]. Adjuvant therapies can reduce the impact of treatment-related side effects in patients treated for extended durations. Patients should be counselled to expect flulike symptoms and to use an anti-inflammatory (e.g. ibuprofen) or an analgesic (paracetamol) to minimise the impact of these bothersome side effects on their daily routine. Psychiatric effects such as irritability, anxiety and depression are more problematic, but can be ameliorated by drug therapy [7,30]. In patients at high risk of psychiatric side effects, adherence to treatment may be maintained by prophylactic use of antidepressants [31,32], combined with a well-trained and supportive clinical team [33,34]. Ribavirin causes dose-related haemolytic anaemia in up to 15% of patients [2,3], which produces fatigue and reduces quality of life. Haematopoietic growth factors, such as recombinant human erythropoietin and granulocyte colony simulating factor, may be used to manage the adverse haematological effects associated with ribavirin and pegylated interferon, respectively. Growth factors reduce the likelihood and severity of these effects and, thus, the need for dose reductions. 5. HIV HCV co-infection Pegylated interferon plus ribavirin is the treatment of choice for chronic hepatitis C in patients with HIV HCV co-infection [35], although there are fewer data available to guide treatment decisions in co-infection than in HCV monoinfection. In APRICOT, the largest trial published to date in this population [36], the overall SVR rate was 40% after 48 weeks of treatment with peginterferon alfa-2a (40 kda) plus ribavirin 800 mg/ day. The overall SVR rate in genotype 1 patients was 29%. In the recently completed PRESCO trial, an overall 49% SVR rate was achieved with peginterferon alfa- 2a (40 kda) plus ribavirin 1000 or mg/day in coinfected patients. The SVR rate in genotype 1 patients was 35% [37]. Whether prolonged treatment can increase SVR rates in HIV HCV co-infected individuals is an, as yet, unresolved issue. In PRESCO, prolonged treatment for 72 weeks produced SVR rate of 53% in patients who were HCV RNA positive at week 4 (vs. 30.1% with 48 weeks; P = 0.04). In contrast, prolonged treatment with peginterferon alfa-2a (40 kda) 180 lg/week plus ribavirin 800 mg/day produced SVR in only one patient randomised to prolonged treatment in another study [24]. The dropout rate in the extension arm was 68%. Extended therapy cannot be recommended in co-infection at this time. 6. Conclusion There is clearly a subgroup of patients the so-called slow responders who benefit from extending combination therapy from 48 to 72 weeks. These patients are readily identified after 4 12 weeks of treatment. Measures to improve adherence to HCV antiviral therapy should be considered when extended treatment is offered, and the potential benefits and risks must be fully discussed in order to prepare patients for the regimen. Waiting until newer therapies become available is an option that some clinicians advocate, but it may be years until new drugs are approved for widespread use. There is no reason to deny these patients the chance of a cure today [38]. References [1] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales Jr FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. 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