Clinical trial: pharmacodynamics and pharmacokinetics of re-treatment with fixed-dose induction of peginterferon α-2a in hepatitis C virus genotype 1 true non-responder patients

Authors


Dr M. Romero-Gómez, Unit for the Clinical Management of Digestive Diseases, Hospital Universitario de Valme, Carretera Cádiz s/n, 41014 Sevilla, Spain.
E-mail: mromerog@supercable.es

Summary

Background  Patients infected with hepatitis C virus genotype 1 who are true non-responders to previous therapy suffer from a very difficult-to-cure disease. New approaches to treatment are necessary.

Aim  To explore the efficacy, pharmacokinetics and safety of fixed-dose induction with peginterferon α-2a and ribavirin in this difficult-to-cure population.

Methods  Seventy-five hepatitis C virus genotype 1 true non-responder patients to a previous interferon-based combination regimen were randomised to receive peginterferon α-2a 360, 270 or 180 μg/week for 12 weeks, followed by 180 μg/week for 36 weeks, in combination with ribavirin (1000/1200 mg/day). Peginterferon α-2a concentration was measured throughout the study.

Results  Sustained virological response rates were 38%, 30% and 18%, in the 360, 270 and 180 μg/week groups, respectively (relapse rates: 25%, 50% and 64%, respectively). The area under the serum concentration-time curve of peginterferon α-2a from 0–12 weeks increased in a dose-dependent manner (P < 0.0001) and was associated with the sustained virological response (odds ratio: 1.35; 95% CI: 0.89, 2.06). The three regimens were equally well tolerated.

Conclusion  Fixed-dose induction of peginterferon α-2a resulted in increased drug exposure and improved the likelihood of achieving a cure, without compromising safety in hepatitis C virus genotype 1 true non-responder patients.

Introduction

Pegylated interferon in combination with ribavirin is the standard of care for patients with chronic hepatitis C. Peginterferon α-2a (PEGASYS; Roche, Basel, Switzerland) plus ribavirin (COPEGUS; Roche) treatment regimens have achieved sustained virological response (SVR) rates as high as 66% in treatment-naïve patients, in randomised controlled clinical trials.1–3 However, SVR rates are heterogeneous, and are negatively influenced by host factors such as older age, advanced fibrosis, high body mass index, insulin resistance, relapse or failure to respond to previous treatment,4 and by viral factors such as hepatitis C virus (HCV) genotype and high baseline viral load.5 Thus, at least half of patients with HCV genotype 1 fail to respond to therapy, and need further treatment options.

For these patients, there are another set of factors to be considered in the identification of patients with the best chance of a cure. The type of failed regimen (interferon alone vs. interferon plus ribavirin) and type of virological non-response during the previous regimen (non-response vs. relapse) may indicate the likelihood of achieving an SVR with further treatment.6 Consequently, patients infected with HCV genotype 1 who are non-responders to initial therapy historically represent a patient group with difficult-to-cure disease.

New approaches to treating patients who have failed therapy are under investigation. Re-treatment of non-responders is a concept validated by several studies in patients with chronic hepatitis C and advanced hepatic fibrosis in which an SVR rate of approximately 15% was achieved.6–10 However, improved treatment schedules are needed. New approaches to treating patients who have failed therapy are underway and include the use of more intensive treatment regimens of pegylated interferon-based therapy, as well as alternative treatments utilising albuferon, consensus interferon,11 and amantadine. In this regard, the use of high induction doses of pegylated interferons and/or the prolonged duration of therapy12, 13 are options that may provide patients who previously failed therapy with the chance of a cure. Here, the efficacy, safety and pharmacokinetic profile of high fixed-dose induction therapy with peginterferon α-2a in combination with ribavirin were investigated in patients with HCV genotype 1 who were non-responders to previous interferon plus ribavirin therapy.

Methods

Study design

This was a randomised, multicentre, open-label, parallel-group pilot study in patients who had failed to respond to at least 22 weeks’ previous treatment with a conventional interferon plus ribavirin combination (defined as positive HCV RNA at every measurement during the whole treatment period – null responder –). Patients were randomised [1:1:1, according to a centralised procedure that was stratified by hepatitis C viral load at screening (≤ or >800 000 IU/mL)] to one of three groups and initially received peginterferon α-2a 180, 270 or 360 μg/week plus ribavirin 1000/1200 mg/day for 12 weeks. The patient randomisation numbers were allocated sequentially in the order in which they were enrolled. It was recommended that patients who failed to achieve an early virological response (EVR), defined as undetectable HCV RNA by qualitative polymerase chain reaction assay (COBAS AMPLICOR™ HCV Test v2.0; Roche Diagnostics, Branchburg, NJ, USA, limit of detection 50 IU/mL) or >2 log10 decline in HCV RNA (COBAS AMPLICOR™ HCV MONITOR Test v2.0, limit of quantification 600 IU/mL) after 12 weeks, discontinued treatment (treatment could, however, be continued for non-EVR patients at the discretion of the investigator). From 12 weeks onwards, patients received peginterferon α-2a 180 μg/week plus ribavirin 1000/1200 mg/day for a further 36 weeks. All patients were followed-up for 24 weeks after treatment completion.

Patients

Patients were eligible for entry if they were aged ≥18 years, and were non-responders to at least 22 weeks of conventional interferon plus ribavirin therapy. Additional inclusion criteria were infection with HCV genotype 1 with a baseline viral load >1000 IU/mL, elevated serum alanine aminotransferase activity for >6 months, and a liver biopsy obtained within the previous 36 months consistent with a diagnosis of chronic hepatitis C. Exclusion criteria were previous treatment with any pegylated interferon, cirrhosis or hepatocellular carcinoma, and prior therapy with systemic anti-viral, antineoplastic or immunomodulatory agents, co-infections with hepatitis A, or B virus or HIV, chronic liver disease other than hepatitis C, decompensated liver disease, haemoglobin <12 g/dL (women) or <13 g/dL (men), increased baseline risk for anaemia, neutrophil count <1500 cells/mm3 or platelet count <90 000 cells/mm3, and serum creatinine level >1.5 times the upper limit of normal. Further exclusion criteria were pregnancy/lactation, major organ transplantation, and evidence of drug abuse (including excessive alcohol consumption) within 1 year of study entry.

Written informed consent was obtained from each patient prior to inclusion in the study, and the study was conducted in accordance with Good Clinical Practice guidelines and in compliance with the Declaration of Helsinki. Ethical approval of the study protocol was obtained from the institutional review board of each participating centre prior to patient recruitment.

Efficacy assessments

The efficacy endpoints were EVR, SVR and relapse rates. SVR was defined as undetectable serum HCV RNA at the end of the 24-week untreated follow-up period. Relapse was defined as the presence of virological response at the end of treatment (week 48) but not at the end of follow-up (week 72).

Viral kinetic and pharmacokinetic analysis

Serial blood samples were collected for determination of HCV-RNA levels and serum peginterferon α-2a concentrations at intervals between day 0 and week 72. The sampling schedule was as follows: Day 0 [within 6 h of the administration of the first dose of study drug (baseline)]; Day 1 (between 18 and 30 h after the first dose of peginterferon α-2a); Day 4 (at any time during that day); Day 7 (within 12 h before the second dose of peginterferon α-2a); Day 8 (between 12 and 36 h before the second dose of peginterferon α-2a); Day 15 (up to 48 h after the third dose of peginterferon α-2a); Day 22 (up to 48 h after the fourth dose of peginterferon α-2a); and Day 29 (up to 48 h after the fifth dose of peginterferon α-2a). Thereafter, for Week 8 and onwards, blood samples were taken at any time during the respective week: at weeks 12, 24, 36 and 48 (while treatment) and at weeks 52, 60 and 72 (follow-up). Peginterferon α-2a was not determined on week 72. Samples were analysed by a central laboratory, and area under the serum concentration–time curve (AUC) was calculated using the linear trapezoid rule (SAS software; SAS Institute, Cary, NC, USA). The relationship between AUC and the peak serum concentration (Cmax) of peginterferon α-2a, from 0 to 12 weeks and 0 to 48 weeks, in relation to virological response was analysed. First and second phase of viral dynamics were arbitrarily defined as the decline of viral load in log10 from baseline to 36 h and from 36 h to day 29, respectively.

Safety assessments

Safety assessments, including vital signs, blood chemistry, haematological analysis, urinalysis, thyroid function test and the recording of adverse clinical events were performed for all patients who received at least one dose of study medication.

Statistical analysis

Analyses were conducted on an intention-to-treat basis, and included all randomised patients who had received at least one dose of either of the study drugs. An analysis of variance (anova) model was used in order to compare parametric quantitative variables among the three treatments groups (the Kruskall–Wallis test was used in order to compare non-parametric quantitative variables).

Logistic regression models were used to evaluate the relationship between AUC and EVR and SVR. The first model considered EVR as the dependent variable and AUC0–12 weeks as the independent variable; the second model considered SVR as the dependent variable and AUC0–12 weeks as the independent variable; and the third model considered SVR as the dependent variable and AUC0–48 weeks as the independent variable. SAS software (SAS Institute) was used throughout.

The study aimed to enrol 75 patients. With 25 patients per group, the precision [95% two-sided confidence interval (CI)] of the estimate of the on-treatment virological response rate (week 12) would be ±18% for a response of approximately 30% and ±20% for a response of 50%. Consequently, the minimal difference in the proportion of responders that would be detectable with the sample size employed would be approximately 25% (when the response in one group is 25%). This difference was deemed to be clinically relevant in a patient group of previous non-responders.

Results

Patients

Seventy-two patients were randomised and received treatment with at least one dose of peginterferon α-2a and ribavirin. Baseline characteristics in the three treatment groups were similar (Table 1).

Table 1.   Demographic, clinical and virological characteristics at baseline
CharacteristicPeginterferon α-2a dose*P-value
180 μg/week
(n = 28)
270 μg/week
(n = 20)
360 μg/week
(n = 24)
  1. ULN, upper limit of normal; BMI, body mass index; ALT, alanine aminotransferase; HCV, hepatitis C virus.

  2. * Induction dose during the first 12 weeks; all groups also received oral ribavirin 1000/1200 mg/day; † Median (First quartile, Third quartile); ‡ Chi-square or Fisher exact test; § anova; ¶ Kruskall–Wallis test; ** Histological findings have been grouped according to necroinflammatory changes (mild, moderate, marked) when performing the inference.

Gender, M/F (% men)21/7 (75)15/5 (75)20/4 (83)0.7709‡
Age (years)†40 (35, 50)44.5 (40, 49.5)41 (32.5, 48.5)0.4815§
Weight (kg)†75.8 (68.8, 80.8)74.1 (64.5, 83.8)79 (72.8, 88)0.3326¶
Height (cm)†170 (164, 176)168 (162, 173)172.5 (169, 177)0.1758§
BMI (kg/m2)†25.7 (24.2, 27.8)26.3 (24.8, 29.7)26.5 (24.3, 28.3)0.6595¶
ALT level, x ULN†1.7 (1.4, 2.5)2.3 (1.6, 4.1)2.7 (1.9, 4.6)0.0891¶
HCV-RNA level, x 103 IU/mL†714 (444, 850)656 (403, 850)753.5 (590, 850)0.3166¶
Patients with HCV-RNA > 800 000 IU/mL, n (%)13 (46)7 (35)11 (46)0.6925‡
Histological findings, n (%)**0.1069‡
 Mild necroinflammatory changes, no fibrosis1 (4)2 (10)2 (8) 
 Mild necroinflammatory changes, portal fibrosis6 (21)4 (20)2 (8)
 Mild necroinflammatory changes, incomplete septa1 (4)1 (5)1 (4)
 Moderate necroinflammatory changes, no fibrosis2 (7)2 (10)3 (13)
 Moderate necroinflammatory changes, portal fibrosis13 (46)5 (25)6 (25)
 Moderate necroinflammatory changes, incomplete septa1 (4)4 (20)4 (17)
 Marked necroinflammatory changes, portal fibrosis  1 (4)
 Marked necroinflammatory changes, incomplete septa  4 (17)
 Other4 (14)2 (10)1 (4)

Sixteen patients withdrew from the study: four because of adverse events, five because of loss to follow-up, and seven because of other reasons. Patient flow is presented in Figure 1.

Figure 1.

 Flow of participants through the study.

Efficacy

EVR rates were related to the dose of peginterferon α-2a, being of 75%, 70% and 68% in the groups that received 360 μg/week, 270 μg/week and 180 μg/week, respectively . Also, SVR rates were higher in the group that received high-dose induction with peginterferon α-2a 360 μg/week (38%) or 270 μg/week (30%) plus ribavirin during the first 12 weeks of treatment, than in those who received the standard dose of peginterferon α-2a 180 μg/week (18%). The high SVR rate achieved by fixed-dose induction with the 360 μg/week dose was driven, in part, by relapse rates that were lower (25%) in this group than in the 270 and 180 μg/week groups (50% and 64% respectively) (Figure 2).

Figure 2.

 Early virological response (EVR) rate, sustained virological response (SVR) rate and relapse rate (at week 72) according to the induction dose of peginterferon α-2a during the first 12 weeks (all patients also received oral ribavirin 1000/1200 mg/day). Error bars indicate 95% confidence intervals.

Pharmacokinetic analysis

The increased efficacy associated with fixed-dose induction peginterferon α-2a plus ribavirin was consistent with the dose-dependent pharmacokinetic findings for Cmax (Figure 3a) and AUC (Figure 3b). Indeed, logistic regression analysis showed that AUC0–12 weeks was associated with both EVR (odds ratio 1.48; 95% CI: 0.88, 2.48) and SVR (odds ratio 1.35; 95% CI: 0.89, 2.06). In the third model, AUC0–48 weeks was also associated with SVR (odds ratio 1.14; 95% CI: 0.92, 1.41).

Figure 3.

 Mean pharmacokinetics of peginterferon α-2a according to the induction dose during the first 12 weeks (all patients also received oral ribavirin 1000/1200 mg/day) (a) peak serum level (Cmax), and (b) area under the serum concentration–time curve (AUC), from time zero to 12 and 48 weeks. Error bars indicate 95% confidence intervals.

In all three treatment groups, steady state serum concentrations of peginterferon α-2a were reached by week 4, and no drug accumulation was observed in any of the three treatment groups.

Viral kinetic assessments

Repeated measurement of serum HCV RNA showed that a rapid and dose-dependent decline of viral load occurred during the first phase (0 to 36 h) at all three dose levels of peginterferon α-2a plus ribavirin (−0.52, −0.75, −0.91 log10 HCV RNA mean reduction in the groups that received peginterferon α-2a 180 μg/week, 270 μg/week and 360 μg/week, respectively, P = 0.14), whereas mean viral load decline was slower during the second phase (36 h to day 29). The greatest decline was in those patients receiving high fixed-dose induction with peginterferon α-2a 360 μg/week (−1.71 log10 vs. −1.30 log10 HCV RNA mean reduction in those who received 180 μg/week or 270 μg/week) plus ribavirin in the first 12 weeks of therapy.

Differences in pharmacokinetics and viral kinetics were noted between sustained responders and patients who did not respond to retreatment. The mean (±s.d.) peak serum concentration of peginterferon α-2a (0–12 weeks) was significantly higher in patients with an SVR than in those who did not respond (54.88 ± 17.61 vs. 44.89 ± 22.57 ng/mL, respectively, P = 0.0468); similar findings were apparent for Cmax 0–48 weeks (data not shown). Interestingly, only among responders the mean decline of HCV-RNA during the first phase (from 0 h to 36 h) was significantly greater in the high-dose induction groups (−1.16 and −1.11 log10 HCV RNA mean reduction in those who received peginterferon α-2a 270 μg/week and 360 μg/week, respectively) than in the standard-dose group (−0.56 log10 HCV RNA mean reduction, P = 0.0436).

Safety assessments

No major safety issues were reported; fixed-dose induction with peginterferon α-2a 360 μg/week and 270 μg/week plus ribavirin were as well-tolerated as standard therapy for 48 weeks. In common with other studies on interferon-based treatment, asthenia, headache, fever, myalgia, and flu-like symptoms were the most frequently reported adverse events (Table 2). Dose reductions of peginterferon α-2a occurred similarly in all groups (39%, 15% and 17% of patients in the 180, 270 and 360 μg/week groups, respectively; P = 0.0999). In the same respective groups, the proportion of patients with at least one ribavirin dose reduction during treatment period were of 32%, 30% and 13% (P = 0.2218).

Table 2.   Summary of adverse events (AE) according to treatment group
 Peginterferon α-2a dose*
180 μg/week
(n = 28)
270 μg/week
(n = 20)
360 μg/week
(n = 24)
  1. * Induction dose during the first 12 weeks; all patients also received oral ribavirin 1000/1200 mg/day; † Four patients withdrew due to an adverse event; depression, neutropenia, and angina pectoris in three patients who received peginterferon α-2a 180 μg/week, and depression in one patient who received 360 μg/week; ‡ Incidence ≥10% in any group.

Any, n (%)27 (96)20 (100)24 (100)
Serious, n (%)3 (11)1 (5)1 (4)
Leading to withdrawal, n (%)†3 (11)0 (0)1 (4)
Most frequent AE (%)‡
 Asthenia466046
 Headache394033
 Fever322546
 Myalgia253033
 Flu-like symptoms252013
 Tiredness141013
 Nausea 42013
 Arthralgia1810 4
 Depression251021
 Insomnia322517
 Irritability111017
 Anaemia1830 4
 Muscle pain182017
 Musculoskeletal pain141517
 Neutropenia291513
 Cough112013
 Pruritus111013
 Diarrhoea 710 8
 Hair loss11 017
 Emotional lability 7 513
 Dermatitis 4 513
 Chills11 0 8
 Pyrosis11 5 0

Discussion

This study confirms that peginterferon α-2a plus ribavirin can eradicate HCV in genotype 1 patients in whom interferon plus ribavirin treatment had failed.6 Fixed-dose induction with peginterferon α-2a 360 and 270 μg/week for 12 weeks plus ribavirin 1000/1200 mg/day followed by the recommended dose of peginterferon α-2a 180 μg/week plus ribavirin 1000/1200 mg/day for the remaining 36 weeks improved SVR rates to 38% and 30%, respectively. This compared favourably to an SVR rate of 18% in the non-responder patients receiving standard dose peginterferon α-2a 180 μg/week plus ribavirin for 48 weeks in this study, and to an SVR of 17% in non-responder patients treated with an induction regimen of high-dose peginterferon alfa-2b (up to 3 μg/kg/week).14 The improvement in SVR rates associated with fixed-dose induction therapy with peginterferon α-2a 270 and 360 μg/week plus ribavirin were reflected in increases in EVR rates. One reason for the high SVR rate achieved with fixed-dose induction with peginterferon α-2a 360 μg/week was the low relapse rate experienced by patients in this group (25%). Indeed, the relapse rate on this arm of the study was lower than that previously reported in non-responders to previous interferon-based therapy who received standard treatment with peginterferon α-2a (180 μg/week) plus ribavirin (41%).6 Interestingly, the relapse rate for patients in the standard treatment arm (180 μg/week) of the present study (64%) was higher than documented relapse rates following re-treatment of non-responder patients in earlier studies (approximately 50%),7, 15, 16 and most likely reflects differences in patient host and viral characteristics.

Patients who were randomised to the 360 and 270 μg/week regimens did not experience any increase in the rate of adverse events, dose adjustments or premature withdrawals, compared to those randomised to the standard regimen (180 μg/week). This finding is encouraging, as it shows that high fixed-dose induction therapy with peginterferon α-2a does not compromise safety, and contrasts with a previous report of a trend toward a higher frequency of adverse events with high-dose therapy with peginterferon alfa-2b.11

As expected, 270 and 360 μg/week induction doses in the first 12 weeks resulted in increased drug exposure of peginterferon α-2a, which was in turn associated with a trend for increased efficacy. Also, significantly higher concentrations of peginterferon α-2a were seen between 0 and 12 weeks (P = 0.0468) in patients who had achieved an SVR compared with patients who had no SVR. These findings are consistent with the fact that most patients who responded received induction doses of peginterferon α-2a and supports the hypothesis that providing more interferon enhances viral clearance which in turn would increase the chance of SVR. The dose-related biphasic decline in HCV RNA resulting from peginterferon α-2a plus ribavirin observed in the non-responder patients enrolled in this study was consistent with viral kinetics previously reported for peginterferon α-2a plus ribavirin therapy in treatment-naïve patients.17

A possible limitation of the present study is that the results of the primary criterion were inconclusive as there were no significant differences in EVR rates among groups. Although multiplicity issues affecting statistical errors are a concern when repeated tests are performed over the same sample, very interesting data about the relationship of peginterferon dose and SVR emerged in the analyses of secondary criteria.

In conclusion, in this study fixed-dose induction with peginterferon α-2a resulted in increased drug exposure and improved the likelihood of achieving an SVR, without compromising safety. Peginterferon α-2a 360 μg/week plus ribavirin showed a significant benefit over standard dosing, and, although the study was small, it provides support for the concept of the use of fixed-dose induction regimes with peginterferon α-2a plus ribavirin. The use of a fixed-dose induction with peginterferon α-2a 360 μg/week is also being examined in the large ongoing randomised international REPEAT study, in 950 patients who had previously failed to respond to peginterferon α-2b plus ribavirin.18 Another study (PROGRESS) will investigate fixed-dose induction therapy with peginterferon α-2a 360 μg/week in patients with difficult-to-cure characteristics (HCV genotype 1, high viral load, bodyweight >85 kg). These studies aim to identify the most effective treatment options for patients who have the greatest medical need.

Acknowledgements

Authors’ declaration of personal interests: Miguel Muñoz-Sánchez is an employee of Roche Farma S.A. Declaration of funding interests: This study was funded in full by Roche Farma S.A. The preparation of this paper was funded in part by Roche Farma S.A. Data analyses were undertaken by Raquel Jerez and Jesús Villoria who are employees of Medicest S.L. and received funding from Roche Farma, S.A. Writing support was provided by Drs Peter R. Turner (t-scimed, Reus, Spain) and Steve Winter (Wolters Kluwer Health, Chester, UK) and funded by Roche Farma S.A.

Ancillary