Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a

Abstract

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.

Abbreviations

ALT,

alanine aminotransferase;

CHB,

chronic hepatitis B;

CHC,

chronic hepatitis C;

HBeAg,

hepatitis B e antigen;

HBsAg,

hepatitis B s antigen;

HBV,

hepatitis B virus;

HCV,

hepatitis C virus;

HRQL,

health-related quality of life;

MCS,

mental component summary;

PCS,

physical component summary;

ULN,

upper limit of normal

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

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 assessments

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).

Statistical analysis

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.

Results

Baseline characteristics

The baseline characteristics of the patients in the CHB and CHC studies are given in Table 1.

Table 1.    Baseline characteristics of patients included in the two chronic hepatitis B virus infection and five chronic hepatitis C virus infection studies of peginterferon α-2a

	CHB HBeAg- positive, Lau et al. (12), n=271	CHB HBeAg- negative Marcellin et al. (13), n=177	CHB overall, n=448, range	CHC study 1, Reddy et al. (14), n=45	CHC study 2, Heathcote et al. (15), n=87	CHC study 3, Pockros et al. (18), n=210	CHC study 4, Zeuzem et al. (16), n=267	CHC study 5, Fried et al. (17), n=227	CHC overall, n=836, range
^* Study in patients exclusively with cirrhosis. CHB, chronic HBV infection; CHC, chronic HCV infection; HBV, hepatitis B virus; HCV, hepatitis C virus.
Male (%)	79	85	79–85	82	72	71	67	67	67–82
Female (%)	21	15	15–21	18	28	29	33	33	18–33
Age (mean, years)	32.5	40.1	32.5–40.1	42.0	47.1	42.7	40.6	42.3	40.6–47.1
Weight (mean, kg)	66.2	71.0	66.2–71.0	87.5	82.4	80.9	74.7	78.9	74.7–87.5
Ethnicity
Asian/oriental (%)	87	60	60–87	–	2	4	9	5	2–9
Caucasian (%)	9	37	9–37	89	86	84	86	83	83–89
Black (%)	1	2	1–2	9	6	6	2	6	2–9
Other (%)	2	<1	<1–2	2	6	6	3	6	2–6
Bridging fibrosis/cirrhosis (%)	18	31	18–31	9	100^*	18	12	15	9–100

The major difference between the CHB and CHC studies was in the ethnic composition of the enrolled populations. The CHB studies enrolled predominantly Asian patients, whereas the CHC studies enrolled predominantly Caucasian patients.

There were more males than females in both the CHB and the CHC studies. Patients in the CHC studies tended to be older and weighed more compared with patients in the CHB studies. Patients in the HBeAg-negative study were older on average than those with HBeAg-positive CHB.

The percentage of patients with advanced fibrosis or cirrhosis varied quite considerably between the individual studies, but the overall rate from the CHB studies (23%) was similar to that of the CHC studies (24%). The proportion of patients with cirrhosis and advanced fibrosis was higher in the HBeAg-negative CHB study (31%) than in the HBeAg-positive CHB study (18%), reflecting the later stage of HBeAg-negative disease in the natural history of CHB.

Dose modifications and discontinuations

The frequencies of premature withdrawal from treatment and of dose modifications are given in Table 2. Fewer patients in the CHB studies prematurely withdrew from treatment than in the CHC studies. The majority of treatment discontinuations in the CHB studies were for safety concerns. In the CHC studies, a higher proportion of patients discontinued for reasons other than safety, including those who discontinued because of an insufficient therapeutic response.

Table 2.   Frequency of treatment discontinuations and dose modifications in the peginterferon α-2a (180 μg) treatment arms of chronic hepatitis B virus infection and chronic hepatitis C virus infection studies

	HBeAg-positive CHB n=271 (%)	HBeAg-negative CHB n=177 (%)	CHB overall n=448 Range (%)	CHC overall n=836^* n=827† Range (%)
^* Intent to treat population. † Withheld or reduced dose on at least one occasion; – not recorded. ‡ ‡Safety population ALT, alanine aminotransferase; CHB, chronic HBV infection; CHC, chronic HCV infection; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus.
Total number of patients who discontinued treatment^*	6	8	6–8	17–33
Discontinuation for reasons other than safety (including lack of therapeutic response)^*	3	1	1–3	7–26
Discontinuation for safety reasons^*	3	7	3–7	7–22
Adverse events	3	5	3–5	6–20
Lab abnormalities	<1	2	<1–2	1–3
Dose modification† for safety reasons‡	40	40	40	–
Adverse events	7	7	7	6–22
Lab abnormalities	37	37	37	13–27
ALT disorder	12	8	8–12	0–3
Neutropaenia	22	17	17–22	11–17
Thrombocytopaenia	9	19	9–19	2–19
Other/not recorded	2	2	2	0–1

While the frequency of treatment withdrawal was lower in the CHB studies, the proportion of patients who had dose modifications for safety reasons was slightly higher in both CHB studies than in the CHC studies. The majority of the dose reductions for safety in the CHB studies were related to laboratory abnormalities. Overall, exposure to peginterferon alpha-2a was high, at 91 and 84% of the total expected study dose, in CHB and CHC studies respectively.

Laboratory abnormalities

The frequency of dose modification for laboratory abnormalities is shown in Table 2. The laboratory abnormalities most frequently associated with dose modification were neutropaenia, thrombocytopaenia or ALT flares. In the CHB studies, dose modifications for laboratory abnormalities were more frequent in patients with bridging fibrosis/cirrhosis (43.7% for F3/4) than in those without (34.5% for F0–2), the difference being largely attributable to dose modifications for thrombocytopaenia.

Alanine aminotransferase flares

While flares in ALT are uncommon in CHC patients, they are not uncommon in patients with CHB and this is reflected in the higher frequency of dose modifications in CHB. Dose modification was recommended if the ALT levels were >10 × ULN and approximately half of all CHB patients with ALT>10 × ULN were managed by dose modification. The incidence of moderate (>5 × ULN) or severe (>10 × ULN) ALT flares was higher in the HBeAg-positive study than in the HBeAg-negative study: 45 vs 37% and 18 vs 12% respectively. Most patients with ALT flares >5 × ULN to <10 × ULN continued treatment unchanged but with careful monitoring. None of the on-treatment ALT flares in the CHB studies were associated with hepatic decompensation. There was no evidence that patients with bridging fibrosis/cirrhosis experienced more severe ALT flares than those without; the incidence of severe on-treatment ALT flares (>10 × ULN) was similar in both groups (16%).

Neutropaenia and thrombocytopaenia

Neutropaenia was the most common laboratory abnormality leading to dose modification in the CHB studies. The number of patients with a neutrophil count <500/mm³ was similar: 12 (4.4%) and six (3.4%) patients in the HBeAg-positive and HBeAg-negative studies respectively. No incidence of neutropaenia was temporally associated with serious or severe infections. Ten patients required permanent dose modification, while five were managed by temporary dose modification; no patient withdrew from treatment as a result of neutropaenia. The incidence of neutropaenia (<500/mm³) was similar in patients with or without bridging fibrosis/cirrhosis (5% for F3/4 and 8% for F0–2).

Thrombocytopaenia was a common reason for dose modification, particularly in patients with HBeAg-negative CHB, reflecting the lower baseline platelet counts of patients with HBeAg-negative vs HBeAg-positive CHB. In the HBeAg-positive study, 25 patients (9%) had nadir platelet counts <50 000/mm³compared with 38 (21%) in the HBeAg-negative study. In total, three patients (one in the HBeAg-positive and two in the HBeAg-negative study) developed platelet counts <20 000/mm³. Two patients did not have any bleeding; the third patient experienced bleeding during the course of fatal thrombotic thrombocytopaenic purpura. The cause of death, however, was not considered by the investigator to be related to therapy. Patients experiencing thrombocytopaenia (<50 000/mm³) had lower baseline platelet counts than in the overall study population; patients with bridging fibrosis/cirrhosis were more likely to develop thrombocytopaenia than non-cirrhotic patients (24% compared with 10%).

Clinical adverse events

The frequencies of common AEs are given in Table 3; the types of AEs were also consistent with those commonly seen during interferon-based therapy. The incidence of AEs was slightly lower in the CHB studies than in the CHC studies. Similarly, the incidence of individual AEs was generally lower in the CHB studies than in the CHC studies, with the exception of pyrexia.

Table 3.   Frequency of common^* and serious adverse events

	HBeAg-positive CHB n=271 n (%)	HbeAg-negative CHB n=177 n (%)	CHB overall n=448 Range (%)	CHC overall n=827 Range (%)
^* Reported at a frequency of at least 20% in one of the peginterferon α-2a treatment arms of the CHB and CHC studies; –, not recorded/frequency of below 5%. † Cerebral haemorrhage on day 81, 16 days after discontinuation of treatment – death considered possibly related to study treatment. CHB, chronic HBV infection; CHC, chronic HCV infection; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus.
Total number of patients with at least one adverse event	240 (89%)	155 (88%)	88–89	95–100
Pyrexia	133 (49%)	105 (59%)	49–59	24–38
Headache	76 (28%)	42 (24%)	24–28	50–60
Myalgia	70 (26%)	47 (27%)	26–27	31–51
Fatigue	108 (40%)	71 (40%)	40	44–67
Alopecia	55 (20%)	24 (14%)	14–20	17–27
Appetite decreased	40 (15%)	31 (18%)	15–18	11–20
Arthralgia	24 (9%)	27 (15%)	9–15	18–41
Diarrhoea	25 (9%)	19 (11%)	9–11	19–31
Dizziness	25 (9%)	15 (9%)	9	13–23
Nausea	24 (9%)	14 (8%)	8–9	21–44
Insomnia	20 (7%)	15 (9%)	7–9	18–33
Injection site inflammation or injection site reaction	24 (9%)	10 (6%)	6–9	10–31
Rigors	19 (7%)	10 (6%)	6–7	23–47
Abdominal pain upper	19 (7%)	9 (5%)	5–7	13–27
Irritability	–	12 (7%)	7	10–29
Depression	13 (5%)	6 (3%)	3–5	16–27
Pain	–	–	–	5–20
Total number of patients with at least one serious adverse event	12 (4%)	9 (5%)	4–5	7–16
Deaths considered related to therapy/total deaths	0	0/1	0/1	1†/3

The rate of depression reported during and up to 8 weeks after treatment in the CHB studies was significantly lower than that in the CHC studies (P<0.001; Fig. 1).The lower incidence of depression in patients with CHB was not explained by ethnic differences in the study populations. Stratification of depression-related events according to Asians and Caucasians showed a significantly lower frequency in Asians compared with Caucasians in both CHB and CHC studies (P=0.003 and 0.027 respectively; Fig. 1).

Figure 1.  Frequency of depression-related adverse events, during treatment and up to 8 weeks post-treatment, in patients treated with peginterferon alfa-2a in CHB vs CHC, stratified according to ethnicity.

The incidence of serious AEs was lower in the CHB studies than in the CHC studies (Table 3). The most common serious AE in the CHB studies was infection (occurring in six patients), whereas the most common serious AE in the CHC studies was severe psychiatric dysfunction (including mania, suicidal ideation, hysteria, suicide attempt, depression and psychosis). Other serious AEs were mostly single cases occurring in a variety of body systems.

A single death was reported in the CHB studies, a case of thrombotic thrombocytopaenic purpura that was considered by the investigator to be unrelated to treatment. In the CHC studies, three deaths were recorded: a case of cerebral haemorrhage on day 81, 16 days after treatment discontinuation, which was considered to be possibly related to peginterferon alpha-2a treatment; two other deaths were considered to be unrelated to therapy.

Effect of peginterferon alpha-2a on health-related quality of life

The mean HRQL component scores at baseline (adjusted for weight and gender) were lower in the CHB studies than for the CHC studies; this difference reached significance for the PCS (P=0.05; Fig. 2). However, after adjusting for baseline score, weight and gender, treatment with peginterferon alpha-2a had a more benign impact on the HRQL of patients with CHB compared with CHC patients (Fig. 3a and b). This was true for both the PCS and MCS scores, while the difference reached significance for the PCS. After an initial decline, the mean PCS and MCS scores returned to baseline levels at the end of the 24-week post-treatment follow-up period in both CHB and CHC patients.

Figure 2.  Mean baseline physical and mental component scores for the pooled CHB and CHC studies.

Figure 3.  A. Change in mean on-treatment physical component scores at week 48 from mean baseline values, stratified according to ethnicity. B. change in mean on-treatment mental component scores at week 48 from mean baseline values, stratified according to ethnicity.

Stratification according to ethnicity showed that the apparent better tolerability of peginterferon alpha-2a in patients with CHB compared with CHC was not a result of ethnic characteristics. Except for the MCS score, peginterferon alpha-2a treatment had less impact on HRQL scores in CHB patients, irrespective of ethnicity.

Discussion

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.

Acknowledgement

This work was supported by a research grant from Roche, Basel, Switzerland.