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Background/Aims: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha-2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). Method: The HBV studies included both hepatitis B e antigen (HBeAg)-positive (n=271) and HBeAg-negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 μg peginterferon alpha-2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health-related quality of life (HRQL) was assessed using the Short-Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24-week treatment-free follow-up period was also included. Results: Differences (HBV vs HCV) were observed in the incidence of AEs (88–89 vs 96–100%), serious AEs (4–5 vs 7–16%) and treatment withdrawals (6–8 vs 17–33%). The frequency of depression-related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. Conclusions: The safety and tolerability of peginterferon alpha-2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon-related AEs and a significantly lower incidence of depression.
Chronic infection with the hepatitis B virus (HBV) and hepatitis C virus (HCV) is a major global health concern. The World Health Organization estimates that chronic hepatitis B (CHB) affects more than 400 million people worldwide and that 170 million people (3% of the world's population) are chronically infected with HCV (1). CHB is associated with serious complications, including liver failure, cirrhosis and hepatocellular carcinoma (2). Likewise, patients with CHC are at risk of developing liver cirrhosis and/or liver cancer.
The health-related quality of life (HRQL) of patients with CHC is known to be impaired (3, 4), but relatively little is known about the impact of CHB on HRQL. A report from Foster et al. (5) suggests that HRQL is impaired in patients with CHB, albeit to a lesser extent than in those with CHC.
A patient's HRQL may be influenced not only by the condition but also by treatment. The current standard of care for patients with CHC, treatment with interferon-based therapy, is associated with varying degrees of adverse events (AEs) such as fatigue, myalgia, flu-like symptoms and alterations in mood (from mild to severe depressive psychosis), which may negatively affect the patient's HRQL in terms of changing their vitality, social interaction and ability to function at work. AE profiles associated with treatment are critical factors in the decision to initiate and maintain therapy, and premature discontinuation of therapy may reflect the impact of treatment-related AEs on HRQL.
Pegylated interferon represents an advancement over conventional interferon because of improved pharmacokinetic/pharmacodynamic properties. A thrice-weekly dosing of conventional interferon is associated with peak/trough-related side effects (6). Pegylation of interferon alpha-2a allows the drug to be maintained at effective levels over a once-weekly dosing period, thereby increasing tolerability. Once-weekly treatment with pegylated interferon alpha-2a has been shown to be associated with a significantly reduced incidence of AEs (e.g. fever, muscle pain, weight loss, depression, lower white blood cell count) compared with once-daily treatment with high-dose consensus interferon (7). Furthermore, treatment with peginterferon alpha-2a has been shown to be associated with significantly less impairment in patient functioning and well-being during treatment than unmodified interferon alpha-2a (8, 9), as determined using the Short-Form 36 (SF-36) scale (10).
Approved agents for the treatment of CHB fall into two categories: (i) immunomodulatory therapies i.e. interferon-based and (ii) antiviral agents (nucleos(t)ide analogues). While the goal of nucleos(t)ide analogue therapy is to suppress HBV DNA replication, the aim of interferon-based therapy is to induce a sustained response to treatment following a finite period of therapy with an agent with both antiviral and immunomodulatory properties. Based on the results of the extensive clinical development programme of pegylated interferon alpha-2a in CHB (11–13), this drug is now approved for the treatment of both HBeAg-positive (12) and HBeAg-negative (13) forms of CHB. Pegylated interferon has now, to a large extent, superceded conventional interferon in the treatment of CHB, because of its improved administration schedule.
The two recent studies evaluating the safety and efficacy of peginterferon alpha-2a in patients with HBeAg-positive and HBeAg-negative CHB have facilitated an analysis of its effects on patient HRQL. A comparison of the safety and tolerability data from the clinical studies of peginterferon alpha-2a in CHB and CHC provides a unique opportunity to investigate the effects of this treatment in patient populations with two distinct but related diseases, and to better understand whether there are differences in how this drug affects patients' HRQL.
Patients and methods
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- Patients and methods
Data were derived from the 180 μg peginterferon alpha-2a monotherapy arms of two large multicentre studies (12, 13) investigating CHB treatment and five multicentre studies in patients with CHC (14–18). Patients in each of the trials were treated once weekly for 48 weeks with peginterferon alpha-2a 180 μg (plus oral daily placebo) and were followed up for a 24-week treatment-free period. Exclusion criteria included: the presence of other liver disease, decompensated liver disease, a coexisting serious medical or psychiatric illness, HCV/HBV coinfection, coinfection with hepatitis D or HIV, neutrophil count <1.5/mm3, platelet count <90/mm3 and serum creatinine >1.5 × upper limit of normal (ULN).
Study centres for the CHB studies were mainly in Asia, with a few in Europe and the United States, and enrolled patients with HBeAg-positive (n=271) or HBeAg-negative (n=177) disease. Patients had tested positive for hepatitis B s antigen (HBsAg) for at least 6 months with an alanine aminotransferase (ALT) value >1 but ≤10 × ULN and a liver biopsy consistent with CHB. Previous anti-HBV treatment was permitted, but not within the 6 months before the study.
Study centres for CHC were mainly in North America, with a few in Europe. Patients were positive for anti-HCV, had an HCV RNA level >2000 copies/mL by PCR, ALT>1 × ULN on two occasions during the preceding 6 months and a pretreatment liver biopsy consistent with CHC. All procedures were approved by the Ethical Committee of Human Experimentation in the appropriate country, and are in accordance with the Helsinki Declaration of 1975.
Safety was assessed by the investigator (by indirect questioning or freely volunteered) at baseline, at weeks 1, 2, 4, 6, 8 and 12 and then every 6 weeks throughout the 48-week treatment period and appropriately during the 24-week treatment-free follow-up period. Any inconsistencies in the definition of an AE between studies are indicated in the appropriate tables where relevant.
An AE was defined as any change from the patient's pretreatment baseline condition, including: inter-current illness, which occurred during the clinical course of this study after treatment had started and up to 8 weeks after the end of treatment, irrespective of whether this was considered by the investigator to be related to peginterferon alpha-2a treatment or not. A serious AE was defined as any event that was fatal or life threatening, required inpatient hospitalization or prolonged hospitalization, resulted in persistent or significant disability or was a congenital anomaly or a birth defect.
Quality of life assessment
Health-related quality of life was assessed using the SF-36 questionnaire of the Medical Outcomes study (10), which has also been validated in Asian patients (19, 20). Responses to the 36 items are used to generate eight domain scores (physical functioning, physical role limitation, pain index, general health perception, vitality, social functioning, emotional role limitation and mental health index) as well as physical component summary (PCS) and mental health component summary (MCS) scores.
The questionnaire was completed at baseline, at treatment weeks 12, 24 and 48, and 24 weeks after the end of the treatment (week 72). The SF-36 scores were available for analysis from both CHB studies (12, 13) and from four of the five studies in CHC (15–18). The mean PCS and MCS scores were calculated for the pooled CHB (n=448) and pooled CHC studies (n=791).
For comparison of HRQL, adjustments were made for gender and weight using sas proc glm and analyses of variance were estimated. Least square mean results were calculated by disease type and racial category (Caucasian or Asian), and t-tests were used to determine the statistical significance of differences in least square means for these two categories. Elsewhere, P values were derived using Fisher's exact test or the χ2 test, where appropriate.
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- Patients and methods
The recent studies in patients with HBeAg-negative and HBeAg-positive CHB demonstrated that peginterferon alpha-2a was well tolerated in these patients, with no unexpected AEs (12, 13). Analysis of data from these large-scale studies has allowed for the first time a unique comparative analysis of this drug in patients with two distinct forms of chronic hepatitis. The results suggest that peginterferon alpha-2a may be better tolerated in patients with CHB compared with those with CHC. While these data are intriguing, we must bear in mind that this comparative analysis is purely observational and, as such, has a number of limitations. However, it does highlight an interesting area of research that could shed further light on the possible basis for these findings.
There may be several reasons to explain why a drug may be tolerated better in one patient population compared with another. HBV and HCV are acquired via different modes of transmission; most patients with CHB tend to acquire the infection early in life, usually perinatally, while many patients with CHC acquire the infection as young adults. It is also conceivable that ethnic origin may also affect how well a drug is tolerated; the CHB study populations comprised a higher proportion of patients of Asian origin.
The exposure to peginterferon alpha-2a in all the studies was high, suggestive of a favourable tolerability profile. The frequency of premature withdrawal in patients with CHB was lower than that observed in patients with CHC. A recent study investigating the safety of peginterferon alpha-2b in patients with HBeAg-positive CHB reported a similarly low frequency of treatment discontinuation as we report here for peginterferon alpha-2a (21).
The low frequency of withdrawals in peginterferon alpha-2a-treated patients with CHB, coupled with the higher frequency of dose modifications for laboratory abnormalities, suggests that the majority of these can be managed by careful monitoring and dose modification: few patients needed to withdraw from treatment. There was no major difference between the frequency of neutropaenia and thrombocytopaenia with respect to dose modification in the CHB and CHC study populations. However, thrombocytopaenia was more common in patients with HBeAg-negative rather than HBeAg-positive CHB, a reflection of the lower baseline counts and the greater proportion of patients with bridging fibrosis/cirrhosis in this group who are at a later stage of disease.
In contrast to CHC, transient flares of ALT levels sometimes exceeding 10 × ULN are not uncommon in patients with CHB and may reflect immune clearance, being indicative of immune-mediated destruction of infected hepatocytes. In HBeAg-positive CHB, flares in ALT have been associated with HBeAg seroconversion – a frequently used therapeutic endpoint (22). In both studies of peginterferon alpha-2a in CHB patients reported here, an association was found between the incidence of severe on-therapy flares (>10 × ULN) and the rates of response 24 weeks post-treatment (12, 13). Flink et al. (23) have recently reported that, while in HBeAg-positive CHB flares were not more common in responders than non-responders to peginterferon alpha-2b, host-induced flares (followed by a decrease in HBV DNA) were highly associated with treatment response. None of the on-treatment flares in patients treated with peginterferon alpha-2a in the CHB studies reviewed here were associated with hepatic decompensation.
There was an overall lower frequency of AEs and serious AEs in the CHB patients. Although the type of common AEs reported were similar in CHB and CHC patients treated with peginterferon alpha-2a, and reflected those known for conventional interferon, the frequency of common AEs was generally lower in patients with CHB than in those with CHC. Indeed, almost all individual AEs were less common in CHB patients, in particular, the frequency of depression-related events. A similar observation was reported previously for conventional interferon alpha (24).
Stratification of depression-related events in the peginterferon alpha-2a studies analysed here showed that they were less frequent in CHB compared with CHC, irrespective of ethnicity. The reasons for the lower rate of depression-related events in patients with CHB are unknown but may include host susceptibility factors or viral factors, such as the ability of HCV to infect the nervous system. A higher incidence of depression-related events was reported in Caucasian patients compared with Asian patients in both CHB and CHC studies, which is consistent with research that shows depression to be sensitive to cultural influences (25). Depression is known to play an important role in the impaired HRQL of CHC patients and is a known side effect of antiviral CHC treatment (28). In addition, mood disorders such as anxiety and depression are thought to contribute to other cognitive impairments commonly reported during interferon-based treatment, such as difficulty in thinking and concentration (29). In contrast to the wealth of data on depression in patients with CHC, there is a lack of information regarding depression and the HRQL of CHB patients.
Evidence from psychometric studies and magnetic resonance spectroscopy suggests central nervous system involvement of HCV infection might explain some of the fatigue, depression/anxiety and impaired HRQL in patients with CHC (25). The contribution of non-liver, co-morbid factors (substance abuse, depression, interferon treatment) to the prevalence and magnitude of impaired cognitive function in patients with CHC may be substantial (28). A recent study in patients with CHC has suggested a direct role of interferon response genes in generating depression during therapy (30). The functional analysis of the differentially regulated genes that were identified in this study could lead to the development of novel therapeutic approaches to reduce the occurrence of major depression in patients with CHC.
The analyses on HRQL were carried out using the well-established SF-36 instrument, which has been validated and culturally adapted for use in various countries and continents, including Asia (19, 20). It is conceivable that life-long infection, rather than infection acquired later in life, may influence the perception of HRQL. Although the mean baseline HRQL composite scores in patients with CHB were lower than those in patients with CHC, the negative impact of peginterferon alpha-2a on HRQL was less pronounced in patients with CHB, compared with those with CHC. The reduction in on-treatment HRQL at week 48 from the baseline value was less pronounced in patients with CHB than with CHC; this difference was significant for the PCS scores. A factor other than ethnicity that may impact on HRQL experienced by patients with CHB or CHC and warrants further study is sociocultural differences. The prevalence of CHB tends to be higher in large families with a lower socio-economic background, where family members and household contacts are at a high risk of acquiring the disease.
In conclusion, this comparative analysis suggests that the safety and tolerability of peginterferon alpha-2a in patients with CHB compare favourably with that observed in patients with CHC, with an overall lower incidence of common interferon-related AEs and, in particular, an apparently lower rate of depression-related AEs. The low rate of withdrawals in CHB patients treated with peginterferon alpha-2a and its reduced impact on HRQL in patients with CHB compared with CHC may be an important consideration for physicians when selecting the most appropriate treatment regimen for their CHB patients.