Introduction
In Japan, the prevalence of the hepatitis C virus (HCV) antibody is highest in the elderly population. In a recent analysis,[1] the average age of HCV-positive patients in Japan was found to be greater than that of US patients by approximately 20 years. Results of the analysis suggested that the introduction of HCV into the Japanese population occurred >100 years ago, followed by wide dissemination in the 1930s and 1940s. In contrast, HCV was introduced into the US 100 years ago, followed by wide dissemination in the 1960s. This extended period of exposure to HCV was the likely reason for the considerably higher prevalence of hepatocellular carcinoma in Japan.
To date, it is unclear if genetic and/or environmental factors have an influence on the incidence of hepatocellular carcinoma in Japan. The duration of HCV infection appears to be an important factor for the development of hepatocellular carcinoma, although the age of patients with post-transfusion HCV has been reported to be a significant factor, regardless of the duration of exposure to HCV.[2] Therefore, it appears to be important for elderly patients to undergo interferon (IFN) therapy in the absence of serious complications such as uncontrolled hypertension or insulin-dependent diabetes mellitus.
Combination therapy with peginterferon (PEG IFN)-α-2a plus ribavirin was found to be more effective than PEG IFN-α-2a monotherapy in Japanese patients with HCV genotype 1b.[3] However, a recent study showed that sustained virological response (SVR) rates were lower in older (≥40 years of age) compared with younger patients with HCV genotype 1b and a high viral load.[4] In addition, inadequate adherence to combination therapy with IFN-α-2b and ribavirin was independently associated with increasing patient age and a reduction in SVR response rates.[5] There are insufficient numbers of clinical trials evaluating the use of PEG IFN plus ribavirin in elderly patients, and an effective dose and treatment period has not been established.
The aim of this retrospective analysis was to investigate the effects of host-related factors (i.e. sex, age, baseline HCV RNA level, bodyweight and fibrosis stage) and PEG IFN-α-2a plus ribavirin dose reductions on SVR rates in patients with a difficult-to-treat form of chronic hepatitis C.
Patients and Methods
We retrospectively analysed data from a phase III, randomized, double-blind clinical trial conducted at 43 Japanese centres between June 2002 and September 2004.[3]
Patients
A total of 192 treatment-naive patients were included in the analysis. Inclusion criteria were Japanese adults aged ≥20 years with an HCV genotype 1b infection, a serum HCV RNA level of ≥1 × 105 IU/mL, an elevated serum alanine aminotransferase (ALT) level of ≥45 IU/L within 6 months of screening, and chronic hepatitis C confirmed by liver biopsy. Patients were excluded if they had neutropenia (<1500 neutrophils/mm3), leucopenia (<3000 cells/mm3), thrombocytopenia (<90 000 platelets/mm3), anaemia (haemoglobin <12 g/dL), a hepatitis B virus co-infection, decompensated liver disease, organ transplant, a creatinine clearance <50 mL/min, poorly controlled psychiatric disease, poorly controlled diabetes, malignant neoplastic disease, severe cardiac or chronic pulmonary disease, immunologically mediated disease, or retinopathy.
Study Design
Patients were randomized according to a 1 : 1 ratio to 48 weeks of treatment with subcutaneous PEG IFN-α-2a (Pegasys®, Roche, Tokyo, Japan)Cited Here... 180 μg/week in combination with either twice daily oral ribavirin tablets (Copegus®, Roche, Basle, Switzerland) or placebo, followed by 24 weeks of untreated follow-up. The ribavirin dosage was 600, 800 or 1000 mg/day in patients with a bodyweight of ≤60, 60-80 or >80 kg, respectively; these dosages were based on the currently used dosages of ribavirin in Japan. Patients were stratified according to HCV RNA level.
Virological Methods
Qualitative and quantitative serum HCV RNA assessments were conducted using the Cobas Amplicor HCV Test PCR assay (version 2.0; limit of detection 50 IU/mL) and the Cobas Amplicor HCV Monitor Test (version 2.0; limit of quantitation, 500 IU/mL), respectively. HCV genotyping was performed according to the method described by Okamoto et al.[6] The presence of serum anti-HCV antibodies was not assessed.
Histology
Liver biopsies were taken within 12 months of enrolment. An independent pathologist evaluated, graded and staged liver biopsy specimens according to the Ishak modified hepatic activity index and the new European classification.[7,8]
Assessment of Efficacy
The primary efficacy end point of the study was the SVR rate, which was defined as a HCV RNA level of <50 IU/mL after 24 weeks of untreated follow-up.
Statistics
The Cochran-Mantel-Haenszel test was used to compare treatment groups, with a significance level of p < 0.05.
Host-related factors associated with an SVR were evaluated using stepwise and multiple logistic-regression models. The following pretreatment factors were considered: sex, age, bodyweight, serum HCV RNA and fibrosis stage (F1/2: mild/moderate; F3/4: severe/cirrhosis). Factors such as the maintenance of a full dosage schedule, the requirement of dose reductions, and treatment discontinuation were also considered.
All patients receiving at least one dose of study drug were included in the efficacy analysis. Patients without follow-up data were considered not to have attained an SVR.
Results
Patient Demographics
A total of 192 patients were randomized to treatment and patient characteristics were similar at baseline in the two treatment groups (table I). Approximately 30% of patients were considered elderly (≥60 years of age).
Table I. Baseline ch...Image Tools
Virological Response
The overall SVR rate was significantly higher in patients who received combination therapy with PEG IFN-α-2a plus ribavirin (57/96 patients; 59.4%; 95% CI 48.9, 69.3) versus PEG IFN-α-2a monotherapy (23/96 patients; 24.0%; 95% CI 15.8, 33.7), resulting in an odds ratio (OR) of 4.65 (95% CI 2.49, 8.69; p < 0.001).
Factors Associated with Sustained Virological Response (SVR)
Following combination therapy, the attainment of an SVR was not influenced by any pretreatment factor (including fibrosis stage, age, sex, HCV RNA level and bodyweight) evaluated in this analysis (table II). In the combination therapy group, the SVR rate tended to be higher in younger males (<50 years of age) versus males aged ≥60 years (figure 1).
Multiple logistic-regression analyses found no significant correlations between host-related factors and the achievement of an SVR with combination therapy.
In contrast, in patients receiving monotherapy, lower baseline HCV RNA levels (OR 1.003; 95% CI 1.006, 1.001; p = 0.006), younger age (OR 1.081; 95% CI 1.125, 1.034; p = 0.0009) and a severe fibrosis stage (OR 6.194; 95% CI 1.037, 37.000; p = 0.0455) significantly increased the likelihood of achieving an SVR.
Effect of Medication Adherence on SVR
In the combination therapy group, patients maintaining a full dosage schedule of PEG IFN-α-2a and ribavirin and those requiring dose reductions of either study drug had similar SVR rates (figure 2). However, the SVR rate was reduced to 33.3% among patients who discontinued combination therapy. Only three of the 31 patients who received the full dosage schedule were ≥60 years of age; the majority of elderly patients failed to complete the full dosage schedule as a result of adverse events. Similarly, of the 15 patients who discontinued combination therapy, three were <50 years of age and six were ≥60 years old.
The SVR rate was reduced in patients receiving <60% of the cumulative PEG IFN-α-2a and ribavirin planned total doses (figure 3). Dose reductions negatively affected the SVR rate in elderly patients who had received <60% of the cumulative PEG IFN-α-2a and ribavirin doses, which was achieved by 0/10 (0%) and 3/13 (23%) patients who were ≥50 years of age, and by 0/6 (0%) and 2/7 (28.6%) patients who were ≥60 years of age, respectively.
Discussion
Combination therapy with PEG IFN-α-2a plus ribavirin was associated with significantly higher SVR rates compared with PEG IFN-α-2a monotherapy, in treatment-naive patients infected with HCV genotype 1b (61% vs 26%; p < 0.001).[3] This outcome is noteworthy, because individuals with HCV genotype 1 infections are considered to be relatively difficult to treat.[9]
Previously, there were no data on the association between sex or age and virological response following treatment with PEG IFN-α-2b plus ribavirin.[10] Our data indicate that the attainment of an SVR following combination therapy was not influenced by any of the pretreatment host-related factors (including age, sex, HCV RNA level, fibrosis stage and bodyweight) evaluated in this retrospective analysis, although younger males (<50 years) appeared to have a higher SVR rate compared with males aged ≥60 years (75% vs 50%). Younger age, lower baseline HCV RNA levels and a severe fibrosis stage significantly increased the likelihood of achieving an SVR with monotherapy. In contrast, a previous study[11] showed that a histological activity index score of >10 and a lack of cirrhosis or bridging fibrosis were independent factors associated with SVR attainment among patients treated with monotherapy, which suggests that severe fibrosis staging negatively impacts the SVR rate. In our study, a severe fibrosis stage was reported in only 15.6% of patients. As a result, the small proportion of patients with severe fibrosis staging may have influenced the outcome of the current analysis.
Anaemia is a common adverse effect that can occur soon after the initiation of treatment with PEG IFN plus ribavirin for HCV infections. This complication can negatively impact patient quality of life, and is the most common reason for dose reductions and the temporary or permanent discontinuation of ribavirin. Such dose modifications have been shown to reduce the efficacy of treatment.[12] In general, females were predicted to have a higher likelihood of becoming anaemic than male patients.[13] In addition, the dose reduction rate of PEG IFN-α-2a and ribavirin is higher in elderly patients, which negatively impacts the achievement of an SVR.[5]
In a recent pooled analysis[14] of two phase III trials of 48 weeks of treatment with PEG IFN-α-2a plus ribavirin, the SVR rate was significantly reduced (p = 0.0006) in patients with a cumulative ribavirin dose of <60%. Prolonged periods of dose reduction, temporary interruptions or premature cessation of ribavirin were also associated with decreased SVR rates.
Previous studies have not assessed the impact of reducing the dose of PEG IFN independent of ribavirin, or differentiated between dose reduction, or interrupting or prematurely discontinuing treatment. An analysis of the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial[15] investigated the impact of PEG IFN-α-2a and ribavirin dose reductions during the retreatment of patients infected with chronic HCV genotype 1 who did not respond to standard IFN with or without ribavirin treatment. A decrease in the cumulative dose of PEG IFN-α-2a received during the first 20 weeks of treatment (lead-in phase), from full dose (≥98%) to ≤60%, reduced the SVR rate from 17% to 5%. In contrast, reducing the dose of ribavirin from full dose to ≤60% did not affect the SVR rate as long as ribavirin administration was not interrupted for more than seven consecutive days. However, the premature discontinuation of ribavirin, even with full-dose PEG IFN-α-2a, reduced the SVR rate to 3%. This suggests that sufficient dosage during the early stages of therapy is required to achieve a high SVR rate with combination therapy. In our study, the SVR rate was also reduced in patients who received cumulative PEG IFN-α-2a and ribavirin doses of <60%, which was further decreased in patients who discontinued combination therapy. Therefore, it is important to alter the way adverse events of PEG IFN-α-2a and ribavirin therapy are managed to minimize the number of patients needing to reduce doses or discontinue therapy.
Conclusion
The attainment of an SVR following PEG IFN-α-2a plus ribavirin combination therapy was not influenced by any of the host-related factors evaluated in this analysis, although males aged ≥60 years tended to have a lower SVR rate. In contrast, younger age, male sex and lower baseline HCV RNA levels significantly increased the likelihood of achieving SVR with monotherapy. Dose reductions had a negative impact on SVR in elderly patients receiving combination therapy. Therefore, it is important to minimize PEG IFN-α-2a and ribavirin dose reductions by effectively managing treatment-related adverse events in elderly patients.
Acknowledgements
The authors are members of the Japanese PEG-IFN-α-2a plus ribavirin phase III study group. This study was funded by Chugai Pharmaceutical Co. Ltd, Japan, through the provision of drugs for the study. The retrospective analysis was supported by a grant from Chugai Pharmaceutical Co. Ltd. No other funding was received. The authors have no conflicts of interest that are directly relevant to the content of this study.
References
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