Worldwide, more than 2 billion people show evidence of infection with hepatitis B virus (HBV) and chronic HBV infection affects about 400 million people [1,2]. It is estimated that between 500,000 and 1 million people die annually due to HBV-associated liver disease, largely because of cirrhosis and hepatocellular carcinoma [3]. Despite the availability of safe and effective vaccines for more than two decades, HBV infection still is a global health problem.
Patients can present with chronic HBV in one of three phases of infection [4]. In the immunotolerant phase of infection, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) are present, HBV-deoxyribonucleic acid (DNA) levels are high, and hepatic inflammation is mild. In the immunoactive phase, HBsAg, HBeAg, and high HBV DNA are still present, while an active immune response results in hepatic inflammation with elevation of serum alanine aminotransferase (ALT). Loss of HBeAg and seroconversion to anti-HBe can occur.The immune-control phase follows HBeAg seroconversion, with minimal hepatic inflammation and low HBV-DNA levels due to a continuous host immune response. However, in an increasing number of HBeAg-negative patients, biochemical and histological activity recur and HBV-DNA levels are high, resulting in HBeAg-negative chronic hepatitis due to HBV variants that hamper the production of HBeAg. The most commonly described mutation is the G to A switch at position 1896 of the pre-core region of the hepatitis B genome. This mutation leads to a translational stop codon in the leader sequence of the HBeAg protein resulting in the inhibition of the protein synthesis.
The natural course of HBV infection and response to antiviral treatment, among other factors such as HBeAg status, serum HBV DNA, and ALT, also seem to depend on HBV genotype. Hepatitis B virus has been classified into eight genotypes (A to H), based on an intergroup divergence of 8% or more in the complete nucleotide sequence [5-7]. Genotypes A and D are most frequently observed in Europe and North America, while genotypes B and C are most prevalent in Asia. Several studies have shown a relation between HBV genotype and the natural course of HBV and response to antiviral therapy [8-11].
Registered treatment for chronic hepatitis B currently consists of (pegylated) interferon (PEG IFN), lamivudine, and adefovir dipivoxil. Entecavir has recently been licensed in several countries and is expected to be in others in the short term. Until the late 1990s, interferon alpha (IFNα) was the only approved antiviral agent for the treatment of chronic HBV. A finite treatment course with interferon-based therapy results in sustained response in about one third of patients. Induction of an HBV-specific immune response seems crucial for persistent control of HBV infection. It has been demonstrated that response to a course of IFNα is durable in the majority of patients and leads to favorable long-term outcome [12,13]. With the availability of nucleos(t)ide analogues, the approach to treatment of chronic HBV has dramatically changed over the past decade. Nucleos(t)ide analogues such as lamivudine, adefovir dipivoxil, and entecavir are potent inhibitors of HBV replication and have an excellent safety and tolerability profile. However, while response to IFN is generally durable, nucleos(t)ide analogue treatment requires indefinite therapy in most patients. Since nucleos(t)ide analogues are well tolerated, prolonged therapy is feasible, but a major drawback is the considerable risk for developing antiviral resistance, which occurs most frequently in lamivudine-treated patients and to a lesser extent during adefovir dipivoxil or entecavir therapy.
Antiviral treatment is generally recommended for chronically infected patients with high serum HBV DNA (above 105 and 104 copies/mL in HBeAg-positive and HBeAg-negative patients, respectively) and persistence of elevated ALT levels over a 3- to 6-month period [3,14]. In this chapter we will discuss the role of PEG IFNα in the treatment of chronic HBV.
ANTIVIRAL ACTIONS OF INTERFERON
IFN was discovered as an antiviral agent during studies on virus interference in the late 1950s. There are multiple, naturally occurring forms of IFN, including IFNα, which is produced by lymphocytes. IFNs are involved in the host's elimination or control of acute and chronic viral infections. The effects of IFNα are predominantly immunoregulatory, but it also has limited direct antiviral effect on HBV. IFNα inhibits viral replication and degrades viral components; it induces the production of interleukins and subsequently T-cell growth; it augments lytic activity of natural killer cells and cytotoxic T-cells; it enhances the expression of antigens by the major histocompatibility complex; and it modulates the production of proinflammatory cytokines. IFNα was licensed for the treatment of chronic HBV in the early 1990s in most countries.
The addition of a polyethylene glycol (peg) molecule to IFN significantly prolongs the half-life, resulting in more sustained IFN activity and a more convenient once weekly dosing. Two PEG IFNs have been studied for the treatment of HBV, a large branched 40 kDa PEG linked to IFNα-2a (PEG IFNα-2a) and a small linear 12 kDa PEG linked to IFNα-2b (PEG IFNα-2b) [15]. PEG IFNα-2a (40 kDa) has a longer half-life (approximately 80 h); it is mainly catabolized in the liver; and it has active breakdown products.The smaller PEG IFNα-2b (12 kDa) has a shorter half-life (approximately 40 h) and may act as a prodrug depot, slowly releasing interferon [16].Both these IFNs were initially investigated for the treatment of chronic hepatitis C infection and have shown similar tolerability and higher rates of sustained viral response compared to conventional IFN [17,18]. PEG IFNα-2a has recently been licensed for the treatment of both HBeAg-positive and HBeAg¬negative chronic HBV as a 48-week course, given by subcutaneous injection once weekly in a dosage of 180 µg. PEG IFNα-2b has so far only been licensed for the treatment of chronic HBV in specific Asian countries.
RESPONSE TO ANTIVIRAL THERAPY
The ideal end point of treatment of chronic hepatitis B would be complete viral eradication. Since this goal is hardly achieved with available antiviral drugs, the main objective is to stop progression of HBV-induced liver injury. Surrogate end points of treatment therefore are seroconversion to anti-HBe or HBeAg negativity, HBV-DNA negativity by PCR (polymerase chain reaction) assay, normalization of serum ALT, and improvement of liver histology.
Response to antiviral treatment can be defined as sustained off-therapy or therapy-maintained response. Sustained off-therapy response is used to evaluate the efficacy of IFN-based treatment strategies, while therapy-maintained response is a commonly used outcome measure in nucleos(t)ide analogue therapy. Biochemical response is defined as a decrease in serum ALT within the normal range. Virological response can be defined as serum HBV DNA below 105 copies/mL or HBV-DNA negativity by sensitive molecular assay and loss of HBeAg (with seroconversion to anti-HBe) in previously positive patients [3]. Histological response is usually defined as a 2-point decrease in necroinflammatory score with no worsening of fibrosis, while some studies also use a decrease in fibrosis score. Complete response is defined as loss of HBsAg with appearance of anti-HBs.
HBeAg response
To date, results of 5 randomized trials of PEG IFN for the treatment of HBeAg-positive chronic HBV have been reported (Table 1). Four of these studies have compared PEG IFN to its combination with lamivudine, to lamivudine monotherapy, or to conventional IFN. One study compared PEG IFN in combination with lamivudine to lamivudine monotherapy. Treatment duration varied among these studies from 24 to 52 weeks, with 24 to 26 weeks of treatment-free follow-up.
 | TABLE 1. Response to PEG IFN and its combination with lamivudine in HBeAG-positive patients |
Loss of HBeAg occurs in 23 to 30% of PEG-IFN-treated patients [19-21] (Figure 1) and 27 to 44% of patients on combination therapy by the end of treatment [19,20]. In one study, HBeAg loss rates at the end of treatment are significantly higher in patients receiving combination therapy than they are with monotherapy (44 vs 29%, p = .01) [19], while another study does not confirm this finding (30 vs 27%) [20]. At the end of follow-up HBeAg loss rates are comparable among treatment groups and vary between 24 and 36% [19-22].
|
 | Figure 1. Response to pegylated interferon (PEG IFN) monotherapy in hepatitis B e antigen (HBeAg)-positive patients. Rates of HBeAg seroconversion, virological response (hepatitis B virus deoxyribonucleic acid [HBV DNA] below 105 copies/mL), normalization of serum alanine aminotransferase (ALT), and hepatitis B surface antigen (HBsAg) seroconversion in HBeAgpositive patients treated with PEG IFNα-2a/2b monotherapy at the end of follow-up. Various assays were used for quantification of serum HBV DNA in these studies [19-22]. |
At the end of a 24- or 48-week course of PEG-IFN monotherapy, 22 to 27% of patients have lost HBeAg and seroconverted to anti-HBe [19-21]. Combination therapy of PEG IFN and lamivudine results in end of treatment HBeAg seroconversion rates between 24 and 60%. HBeAg seroconversion rates may be higher in PEG IFN plus lamivudine-treated patients compared to patients treated with PEG IFN alone at the end of treatment [19-21]. However, this difference is not observed at the end of follow-up [19,20].
Two studies show higher response to PEG IFN than conventional IFN. One study shows that PEG IFN is superior to conventional IFN in inducing HBeAg loss (37 vs 30% at the end of treatment and 30 vs 27% at the end of follow-up, p = .04) [21], the other found a higher combined response rate (loss of HBeAg, HBV DNA <500,000 copies/mL, and normalization of ALT) in PEG-IFN-treated patients than was found in IFN-treated patients (p = .04) [22].
HBV-DNA response
In both HBeAg-positive and HBeAg-negative patients, suppression of serum HBV DNA is an important outcome measure of antiviral treatment, since lower HBV DNA is associated with lower rates of progression to cirrhosis and hepatocellular carcinoma and thereby improved long-term outcome [23,24].
At the end of treatment, suppression of HBV-DNA levels below 105 copies/mL can be observed in 29 to 52% of HBeAg-positive patients treated with PEG IFN alone (see Figure 1) [19-21], compared to 74 to 86% of patients treated with PEG IFN and lamivudine combination therapy [19,20]. After a 24-week follow-up period, the proportion of patients with HBV DNA below 105 copies/mL is comparable between the treatment groups and varies between 27 and 39% [19-22]. A decline in serum HBV DNA below the lower limit of detection by quantitative PCR assay occurs in 10 to 25% of PEG-IFN-treated patients by the end of treatment. Addition of lamivudine significantly increases this rate from 33 to 69%. However, end of follow-up analysis shows that the advantage of added lamivudine is not durable, with comparable rates of PCR negativity in both groups (6 to 14%) [19,20,25].
The serum HBV DNA in HBeAg-negative patients is below 20,000 copies/mL in 81% of PEG-IFN-treated patients and in 92% of patients receiving PEG IFN and lamivudine combination therapy (Figure 2). At the end of follow-up these rates are 43 and 44%, respectively [26]. Suppression of HBV DNA below 400 copies/mL at the end of treatment occurs more frequently in patients on combination therapy (87 vs 63% in the PEG-IFN monotherapy group), while this difference is not observed at the end of follow-up (19 vs 20%, respectively) [26].
 | Figure 2. Response to pegylated interferon (PEG IFN) with or without lamivudine (LMV) in HBeAg-negative patients. This figure shows the virological (hepatitis B virus deoxyribonucleic acid [HBV DNA] <20,000 copies/mL) and biochemical response (normalization of alanine aminotransferase [ALT]) rates in HBeAg-negative patients treated with PEG IFNα-2a with or without lamivudine at the end of treatment and the end of followup [26]. Although end-of-treatment response occurs more frequently in patients receiving combination therapy, this increase in response rates compared to PEG-IFN monotherapy is not maintained during post-treatment follow-up. |
Biochemical response
Elevated ALT levels are an indirect marker of hepatic inflammation. In HBeAg-positive patients, normalization of ALT at the end of treatment occurs in 32 to 51% of patients assigned either PEG-IFN monotherapy (see Figure 1) or combination therapy with lamivudine [19-21,25]. After 24 weeks of follow-up a comparable rate of 32 to 50% can be observed [19-22,25].
At the end of treatment, the proportion of HBeAg-negative patients with normalized ALT levels is 38% with PEG-IFN therapy compared to 49% with PEG IFN and lamivudine (see Figure 2). At post-treatment follow-up these rates are 59 and 60%, respectively [26]. Combined biochemical and virological response (HBV DNA <20,000) is an important outcome measure in HBeAg-negative patients and occurs in 36% of PEG-IFN-treated patients and in 49% of patients receiving combination therapy at the end of treatment. The increase in biochemical and virological response with combination therapy compared to PEG IFN alone is not observed at the end of follow-up (Figure 2) [26].
Histological response
Histological response is usually defined as a 2-point decrease in necroinflammatory score (range 0 to 18) or a 1-point decrease in fibrosis score (range 0 to 6), according to the histological activity index [27]. In HBeAg-positive patients, 49 to 53% of patients have improvement of liver histology after a 1-year course of PEG IFN [19,20]. The proportion of patients with improved liver histology is significantly higher in HBeAg-responders compared to nonresponders [28,29]. Among patients with HBeAg loss, 78% had a decrease in necroinflammation and 39% a decrease in fibrosis, compared to 43 and 15% of nonresponders (p = .01 and p = .04 for responders compared to nonresponders, respectively) [29]. Patients with normalization of ALT after therapy also have an increased likelihood of improvement in necroinflammatory score compared to patients with persistence of elevated ALT (76 vs 40%, p = .01) [29].
In HBeAg-negative patients, a 2-point decrease in necroinflammatory score can be observed in 55% of PEG-IFN-treated patients at the end of follow-up and a decreased fibrosis score in 15% [26]. Among virological responders (HBV DNA <20,000 at week 72), the combined histological response rate was 73% in comparison to 49% in nonresponders (p <.001). As in HBeAg-positive patients, normalization of ALT is associated with higher rates of histological response [26]. Reversal of cirrhosis has been observed in 35% of cirrhotic HBeAg-negative patients (13/37 patients) after PEG-IFN therapy [28].
No additional benefit on histological response was observed from the addition of lamivudine in either HBeAg-positive or HBeAg-negative patients [19,20,26,28,29].
HBsAg response
The ultimate goal of antiviral therapy is inducing loss of HBsAg with seroconversion to anti-HBs, since this represents complete control of the virus by the host's immune system. In HBeAg-positive patients, treatment with PEG-IFN monotherapy results in HBsAg seroconversion in 3 to 5% of patients (see Figure 1) [19,20]. HBeAg-responders are more likely to achieve HBsAg seroconversion, with rates of about 10 to 19% [30,31]. Furthermore, higher rates of HBsAg seroconversion have been observed in Caucasian patients as compared to Asians (17 vs 2%, p <.0001) [31]. Addition of lamivudine does not increase HBsAg seroconversion rates. HBsAg seroconversion occurs in 3% of HBeAg-negative patients treated with PEG IFN alone and 2% of patients treated with added lamivudine. Achievement of combined response (HBV DNA <20,000 and normalization of ALT) increases the rate of HBsAg seroconversion in HBeAg-negative patients to 6% [31].With increased follow-up, and in parallel to standard IFN, more patients undergoing HBeAg seroconversion may develop HBsAg seroconversion [13].
Predictors of response
Studies of treatment of chronic HBV with conventional IFN and lamivudine have identified several factors predicting response. These factors include high-pretreatment ALT, low-pretreatment HBV DNA, high degree of necroinflammatory activity, and infection at adult age [3]. For IFN therapy, HBV genotype also influences response rates, with infection with genotypes A and B resulting in higher response rates than with genotypes C and D [10,11].
Baseline factors that are predictive of response to PEG-IFN therapy in HBeAg-positive patients include low viral load [19,32], high ALT concentrations [19,32], absence of previous interferon therapy [19], low HBeAg level [32], and HBV genotype [19]. In HBeAg-negative patients, low baseline HBV DNA and high baseline ALT levels also independently predict biochemical and virological response after 24-week treatment-free follow-up (p = .005 and p = .001) [33]. The role of HBV genotype as a predictor of response to PEG IFN will be discussed separately.
ALT flares and response to PEG IFN
PEG IFN can precipitate immunological flares, with subsequent elevation in serum ALT (ALT flares). Various definitions of ALT flare have been given: a rise in serum ALT to at least 3 to 5 times upper limit of normal (ULN) is predominantly used [34,35]. In untreated patients, the chance of HBeAg seroconversion during ALT flares rises with increasing serum ALT levels [36]. A similar pattern can be observed for HBeAg seroconversion during or after PEG-IFN therapy, which occurs more frequently in patients with elevations of ALT above 5 × ULN than those with maximum ALT levels below this level (p = .03) [37]. During PEG-IFN therapy two types of flares have been distinguished: host-induced flares (a flare followed by a decrease in HBV DNA) and virus-induced flares (a flare preceded by a rise in HBV DNA). Of HBeAg-positive patients with host-induced flares, 58% responded, whereas only 20% of patients with virus-induced flares responded (p = .008) [34].
In HBeAg-negative patients, on-treatment elevations of ALT above 5 × ULN occur in 25% of patients, and 12% of patients have elevation of ALT above 10 × ULN. After therapy, ALT flares above 5 × ULN and 10 × ULN occur in 12 and 7% of patients, respectively [35]. Sustained ALT response at 24 weeks post-treatment is more likely to occur in patients with marked elevations during therapy than it would in patients with minimal or no elevation of ALT level (73 vs 59%, respectively). ALT flares after therapy, in contrast, are associated with a lower likelihood of sustained ALT response (23 vs 59%, respectively) [35]. Furthermore, patients with HBsAg seroconversion tended to have higher on-treatment ALT activity than did HBsAg nonresponders [35].
Hepatitis B virus genotype and response to PEG IFN
The frequency of the most prevalent HBV genotypes (A-D) differs across the large pivotal trials of PEG IFN for chronic HBV, as these studies were performed in different geographic regions. Among HBeAg-positive patients, almost all patients in the study by Lau et al were infected with HBV genotype B (28%) or C (59%) [20], while genotypes A and D were predominant in the Janssen et al study (33 and 39%, respectively) [19]. In the HBeAg-negative study, genotypes B (24%), C (37%), and D (31%) are most prevalent [38].
As previously shown in treatment with conventional IFN [10,11], HBV genotype also seems to influence response to PEG IFN. In the study by Janssen et al, HBeAg-positive patients showed a significant difference in response rate across HBV genotypes, as well as after multivariate analysis. Loss of HBeAg occurs significantly more often in patients with genotype A than it does with genotype D (47 vs 25%, p = .01; Figure 3), while genotype B infection tends to result in higher response rates than does genotype C [19]. Not only is HBeAg loss genotypedependent but so is HBsAg loss, with genotype A patients more likely to lose HBsAg than are patients with genotype D (14 vs 2%, p = .006) [30]. In a predominantly Asian population, HBeAg seroconversion rates were shown to be comparable between genotypes B and C [20]. However, in the limited number of patients with genotype A (23) or D (9), HBeAg seroconversion seems more likely to occur in patients with genotype A (52%) than it seems with D (22%) [20]. HBsAg seroconversion rates in this study are also significantly different across genotypes [31]. Patients with genotype A are more likely to achieve complete response than are patients with genotype B (17 vs 0.6%, p <.001) and tend to have higher response rates compared to genotype D (17 vs 0%, p = .08) [31].
 | Figure 3. Hepatitis B e antigen (HBeAg) loss (A) and hepatitis B surface antigen (HBsAg) loss (B) rates by genotype in patients treated with pegylated interferon (PEG IFN; with or without lamivudine). This figure shows HBeAg loss and HBsAg loss rates at the end of follow-up in HBeAg-positive patients treated with PEG IFNα-2b with or without lamivudine [19], and HBeAg seroconversion and HBsAg seroconversion rates for patients treated with PEG IFNα-2a with or without lamivudine [20]. In the Janssen et al study, HBeAg loss and HBsAg loss rates were significantly higher in genotype A-infected patients as compared to genotype D-infected patients (p = .01 and p = .006, respectively), while response rates tended to be higher in patients with genotype B than they were in those with genotype C [19,30]. In the Lau et al study, HBeAg seroconversion rates tended to be higher in patients harboring genotype A than they were with genotype D. HBsAg seroconversion rates were significantly higher in genotype A-infected patients as compared to genotype B or C (p <.001) [20,31]. |
In HBeAg-negative patients treated with PEG IFN or its combination with lamivudine, sustained response at week 72 (HBV DNA <20,000 copies/mL) occurs more often in patients with genotype C (58%) than it does with genotypes A (33%), B (43%), or D (29%) (p <.04 for genotype C vs A, B, or D) [33,38]. Virological response rates are also higher in genotype B infection than they are in genotype D (p = .05). As in HBeAg-positive patients, HBsAg seroconversion rates seem genotype-dependent in HBeAg-negative HBV. HBeAg-negative patients with genotype A (14%) are more likely to achieve complete response than are those with genotypes B (4%), C (2%), or D (0%) (p <.02 for genotype A compared to genotypes B, C, or D) [31]. HBsAg seroconversion rates tend to be higher in genotype B infection than they are in genotype D (p = .08). Complete response in HBeAg-negative patients may, however, have occurred in patients who spontaneously seroconverted to anti-HBe shortly before inclusion and subsequently developed HBsAg seroconversion.
Influence of prior nucleos(t)ide analogue therapy on response to PEG IFN
A recent study shows marginal efficacy of PEG-IFN therapy in patients who have previously been exposed to lamivudine and developed antiviral resistance (with confirmed mutations in the YMDD motif of the polymerase gene) [39]. Of 16 patients, only 2 (12.5%) had HBeAg seroconversion. These 2 patients were the only ones with a faint signal on the lamivudine-resistance assay compared to a strong signal in all other patients. This study may suggest that the presence of (a major population of) lamivudine-resistant HBV reduces the efficacy of PEG-IFN treatment. Other studies that investigate previous nucleos(t)ide analogue therapy in general rather than confirmed antiviral resistance could contradict this finding. In HBeAg-positive patients, sustained HBeAg loss occurs equally in naïve patients (38%) and lamivudine-treated patients (23%, p = .16 vs naïve patients) [40]. A study in both HBeAg-positive and HBeAg-negative patients previously treated with lamivudine (71%), adefovir dipivoxil (26%), or both (3%) also shows no decrease in response rate to PEG IFN compared to other studies. In HBeAg-positive patients, 37% lose HBeAg and 32% seroconvert to anti-HBe during treatment. In HBeAg-negative patients, 81% have HBV-DNA suppression <105 copies/mL and 80% normalize ALT by the last off-treatment visit [41]. Furthermore, a subgroup analysis of HBeAg-positive patients treated with PEG IFN in the study by Lau et al also does not show differences in HBeAg seroconversion rates between patients with and without previous exposure to lamivudine [42]. In these studies, presence of genotypic resistance to lamivudine was, however, not determined.
SAFETY
Treatment with conventional IFN is associated with considerable side effects. Frequently reported side effects include flu-like syndrome, fatigue, headache, myalgia, and local reaction at the injection site. Other clinically relevant side effects, such as depression, irritability, anorexia, insomnia, thyroid dysfunction, and hepatitis flares, occur less frequently. Severe adverse events include depression, suicide attempts, severe neutropenia, and hepatic decompensation. The most frequently observed adverse events during PEG-IFN therapy are those known to occur with conventional IFN [20,22,25,26,43]. Most side effects are pronounced at the beginning of therapy and appear to subside over time [43]. Adding lamivudine does not influence the occurrence of side effects [20,26,43].
PEG IFN can also cause transient bone marrow depression with decreased neutrophil, leukocyte, and platelet counts. Neutropenia occurs in 17 to 26% of patients and thrombocytopenia occurs in 12 to 19%, at some point during therapy [26,43]. These hematological abnormalities are common reasons for dose modification, with neutropenia being the cause of dose reduction in 52% of patients and thrombocytopenia in 10% [43]. Other frequently reported reasons for dose adjustment include flu-like syndrome and psychiatric disorders. Discontinuation of PEG-IFN therapy for safety reasons is necessary in 2 to 8% of patients [20,22,26,43]. Low neutrophil count (<3 × 109/L) and presence of cirrhosis at baseline predict early discontinuation or dose reduction in PEG-IFN therapy (p = .03 and p = .001, respectively) [43].
Overall, PEG IFN is well tolerated, although dose reduction is necessary in some cases. Counseling patients about the course of these adverse events and adequate supportive treatment may lead to decreased occurrence of early treatment discontinuation.
OPTIMAL DURATION OF THERAPY
PEG IFN is registered for the treatment of chronic HBV as a 1-year course, the treatment duration used in most PEG-IFN trials conducted so far. Typically, conventional IFN was given for 12 to 24 weeks in HBeAg-positive patients and for more than 12 months in HBeAg-negative patients. This raises the question of whether PEG IFN could also be given for short periods in HBeAg-positive patients or should be given for long periods in HBeAg-negative patients. In two studies, PEG IFN was given for 24 weeks [21,22]. Both studies compared PEG IFN to conventional IFN and showed that response rates are higher in PEG-IFN-treated patients than it is in those receiving conventional IFN. Both studies have been criticized because of the low dosage given in the standard IFN arms. Although comparing these findings with those of other studies must be undertaken with caution, as patient populations and therapy doses differ between studies, response to 24 weeks of PEG IFN in the HBeAg-positive appears in the range of those in other studies with longer durations of therapy [19-22]. Data on treatment regimens other than a 48-week course are not available for HBeAg-negative patients.
Durability of response
Studies of the long-term benefits of treatment with conventional IFN show that response is durable in the majority of HBeAg-positive patients, with reactivation in only 10 to 20% [13,44]. However, IFN-induced response is less durable in HBeAg-negative patients. Response to conventional IFN is sustained in about 50% of HBeAg-negative responders [45]. Since trials of PEG IFN for chronic hepatitis B have been performed only in the last few years, duration of post-treatment follow-up in these studies is still limited.
Chan et al reported on sustained HBeAg-response in HBeAg-positive patients treated with PEG IFN and lamivudine combination therapy [46]. At the end of treatment, 60% of patients lost HBeAg; at the end of follow-up of the initial study this rate was 36%. As seen in other studies, a proportion of patients treated with PEG-IFN/lamivudine combination therapy who achieve HBeAg loss at the end of treatment will revert to HBeAg positivity during a 24-week follow-up period, while response to PEG-IFN monotherapy is generally durable [19,20,46]. Eighty-eight percent of patients with HBeAg response at 24-weeks post-treatment remain HBeAg-negative throughout the 76-week follow-up period [46]. In a study by Lau et al on a subgroup of patients treated with PEG-IFN monotherapy, 86% of patients with HBeAg response at 24 weeks post-treatment remain HBeAg-negative throughout a 1-year post-treatment follow-up period. An incremental response rate of 14% was observed after the initial 24-week follow-up period [47].
In HBeAg-negative patients treated with PEG IFN, biochemical response at week 24 post-treatment is maintained in 58% of patients after 2 years of follow-up [48]. In these patients, HBV-DNA levels remain below 105 copies/mL throughout the observation period. At 2 years post-treatment, 6% of patients cleared HBsAg and all but one also seroconverted to anti-HBs [48]. Loss of HBsAg occurs significantly more often in patients with genotype A than it does in those with genotype D after 2 years of follow-up (28 vs 0%, p = .05) [48].
SUMMARY
The approach to treatment of chronic hepatitis B has changed rapidly over the past decade. The treatment landscape has advanced with the availability of multiple new antiviral agents. However, despite this major progress, long-term off-treatment control has not been achieved in a large proportion of patients. IFNα has been the mainstay of therapy for both HBeAg-positive and HBeAg-negative hepatitis B since the early 1990s. An advantage of PEG IFN is that it can be administered once weekly, with a safety profile comparable to IFNα. PEG IFN was found to be superior to lamivudine and conventional IFN regarding sustained off-treatment response [20-22,26], although its superiority to IFNα could be debated since IFN was given at a low dose of 3 to 4.5 MU thrice weekly in these studies [21,22].
A 1-year course of PEG IFN results in sustained HBeAg or virological response in more than one-third of HBeAg-positive and HBeAg-negative patients. Sustained response is associated with improvement of liver enzyme abnormalities and liver histology and, more importantly, with an increased likelihood of HBsAg loss compared to nonresponders.
In an attempt to further increase response rates, the addition of lamivudine to PEG-IFN therapy has been studied. Although this combination of drugs induces greater viral suppression at the end of treatment compared to PEG-IFN monotherapy, it does not improve sustained response at the end of follow-up. Combination with newer nucleos(t)ide analogues and different treatment regimens may lead to higher sustained response rates and should be studied in future trials. Studies of PEG IFN and adefovir dipivoxil combination therapy have already started.
Optimal duration of PEG-IFN therapy has not been established yet. Although response rates to a 24-week course of PEG-IFN [21,22] seem comparable to those observed after 1- year of therapy [19,20], comparisons of these studies must be interpreted with caution. Future studies designed to compare various durations of therapy are needed to determine the optimal duration of treatment for both HBeAg-positive and HBeAg-negative patients.
Although hampered by side effects, PEG IFN still offers the highest chance of sustained off-treatment response for a large group of patients with chronic hepatitis B. Treatment with this drug is therefore preferable as first-line therapy in eligible patients with a high likelihood of response.This group includes patients with high baseline serum ALT (above 2 × ULN) and moderate HBV-DNA levels (105 - 108 copies/mL) and genotype A or B. HBV genotype may become more important in the management of chronic hepatitis B. For patients with a low likelihood of response to, or not eligible for, PEG-IFN therapy, patients not tolerating PEG-IFN therapy, or those with persistent hepatic inflammation and high viral load after a 1-year course of PEG IFN, treatment with nucleos(t)ide analogues can be considered.
REFERENCES
1. Kane M. Global programme for control of hepatitis B infection. Vaccine 1995;13(Suppl 1):S47-S49. [Medline]
2. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733-1745. [Medline]
3. de Franchis R, Hadengue A, Lau G, et al. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol 2003;39(Suppl 1):S3-S25. [Medline]
4. Wong SN, Lok AS. Treatment of hepatitis B: who, when, and how? Arch Intern Med 2006;166(1):9-12. [Medline]
5. Arauz-Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol 2002;83(8):2059-2073. [Medline]
6. Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection? Hepatology 2004;40(4):790-792. [Medline]
7. Stuyver L, De Gendt S, Van Geyt C, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol 2000;81(1):67-74. [Medline]
8. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118(3):554-559. [Medline]
9. Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002;123(6):1848-1856. [Medline]
10. Erhardt A, Blondin D, Hauck K, et al. Response to interferon alpha is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut 2005;54(7):1009-1013. [Medline]
11. Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 2002;36(6):1425-1430. [Medline]
12. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334(22):1422-1427. [Medline]
13. van Zonneveld M, Honkoop P, Hansen BE, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39(3):804-810. [Medline]
14. Manesis EK, Papatheodoridis GV, Sevastianos V, Cholongitas E, Papaioannou C, Hadziyannis SJ. Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection. Am J Gastroenterol 2003;98(10):2261-2267. [Medline]
15. Craxi A, Cooksley WG. Pegylated interferons for chronic hepatitis B. Antiviral Res 2003;60(2):87-89. [Medline]
16. Kozlowski A, Charles SA, Harris JM. Development of pegylated interferons for the treatment of chronic hepatitis C. Bio Drugs 2001;15(7):419-429. [Medline]
17. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958-965. [Medline]
18. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13):975-982. [Medline]
19. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365(9454):123-129. [Medline]
20. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352(26):2682-2695. [Medline]
21. Zhao H, Si CW, Wei L, et al. A multicenter, randomized. openlabel study of peginterferon alfa-2b vs interferon alfa-2b for the treatment of Chinese patients with HBeAg+ve chronic hepatitis B. J Hepatol 2006;44(Suppl. 2):S20-S21.
22. Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen¬positive chronic hepatitis B. J Viral Hepat 2003;10(4):298-305. [Medline]
23. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295(1):65-73. [Medline]
24. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130(3):678-686. [Medline]
25. Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142(4):240-250. [Medline]
26. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351(12):1206-1217. [Medline]
27. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1(5):431-435. [Medline]
28. Cooksley G, Lau GKK, Marcellin P, et al. Peginterferon alpha-2a (40kDa) (Pegasys®) reverses cirrhosis, improves fibrosis and slows progression of fibrosis in patients with HBeAg-positive of HBeAg-negative chronic hepatitis B (CHB). J Hepatol 2006;44(Suppl. 2):S182.
29. van Zonneveld M, Zondervan PE, Cakaloglu Y, et al. Peginterferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine. Liver Int 2006;26(4):399-405. [Medline]
30. Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. Treatment with peg-Interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006;101(2):297-303. [Medline]
31. Hadziyannis S, Lau GKK, Marcellin P, et al. Sustained HBsAg seroconversion in patients with chronic hepatitis B treated with peginterferon alpha-2a (40kDa) (Pegasys®). J Hepatol 2005;42(Suppl 2):S178.
32. Cooksley G, Lau GKK, Liaw YF, et al. Effects of genotype and other baseline factors on response to peginterferon α-2a (40 kDa) (Pegasys®) in HBeAg-positive chronic hepatitis B: results from a large, randomised study. J Hepatol 2005;42(Suppl.2):S30.
33. Bonino F, Lau GKK, Marcellin P, et al. The first detailed analysis of predictors of response in HBeAg-negative chronic hepatitis B: data from a multicenter, randomized, partially double-blind study of peginterferon-alfa-2a (4-KD) (Pegasys®) alone or in combination with lamivudine vs lamivudine alone. Hepatology 2004;40(S4):A1142.
34. Flink HJ, Sprengers D, Hansen BE, et al. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy. Gut 2005;54(11):1604-1609. [Medline]
35. Piratvisuth T, Marcellin P, Lau GKK, et al. ALT flares and sustained response in patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40KD) (Pegasys®), peginterferon alfa-2a (40KD) plus lamivudine or lamivudine. Hepatology 2005;40(S4):A1137.
36. Yuen MF, Yuan HJ, Hui CK, et al. A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy. Gut 2003;52(3):416-419. [Medline]
37. Piratvisuth T, Luo KX, Marcellin P, et al. Effect of ALT flares on efficacy and safety of peginterferon alfa-2a (40KD) (Pegasys®), peginterferon alfa-2a plus lamivudine and lamivudine in HBeAg-positive chronic hepatitis B (CHB). J Hepatol 2005;42(Suppl. 2):189-190.
38. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a (40KD) (Pegasys®) monotherapy is more effective than lamivudine monotherapy in the treatment of HBeAg-negative chronic hepatitis B: 72-week results from a phase III, partially double-blind study of Pegasys® alone vs Pegasys® plus lamivudine vs lamivudine. J Hepatol 2004;40(Suppl. 1):S34.
39. Leemans WF, Flink HJ, Janssen HL, Niesters HG, Schalm SW, de Man RA. The effect of pegylated interferon-alpha on the treatment of lamivudine resistant chronic HBeAg positive hepatitis B virus infection. J Hepatol 2006;44(3):507-511. [Medline]
40. Flink HJ, Hansen BE, Van Zonneveld M, Schalm SW, Janssen HLA. Successful treatment with pegylated interferon alpha-2b in HBV non-responders to standard IFN and lamivudine. Hepatology 2005;40(S4):663A.
41. Marcellin P, Boyer N, Piratvisuth T, et al. Efficacy and safety of peginterferon alpha-2a (40KD) (Pegasys®) in patients with chronic hepatitis B who had received prior treatment with nucleos(t)ide analogues - the PEGaLAM cohort. J Hepatol 2006;44(Suppl.2):S187.
42. Lau GKK, Piratvisuth T, Luo KX, et al. Peginterferon alpha2a versus peginterferon alpha2a plus lamivudine versus lamivudine in HBeAg-positive chronic HBV: effect of previous treatment and drug exposure on sustained response. J Hepatol 2005;42(Suppl. 2):S15.
43. van Zonneveld M, Flink HJ, Verhey E, et al. The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther 2005;21(9):1163-1171. [Medline]
44. Krogsgaard K. The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B. The Long-Term Follow-up Investigator Group. The European Study Group on Viral Hepatitis (EUROHEP). Executive Team on Anti-Viral Treatment. J Viral Hepat 1998;5(6):389-397. [Medline]
45. Papatheodoridis GV, Manesis EK, Hadziyannis S. Long-term follow up after initial response to interferon therapy in patients with HBeAg negative chronic hepatitis B. Hepatology 2000;32:378A.
46. Chan HL, Hui AY, Wong VW, Chim AM, Wong ML, Sung JJ. Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology 2005;41(6):1357-1364. [Medline]
47. Lau DT, Piratvisuth T, Luo KX, et al. Durability of response and occurrence of late response to peginterferon alpha-2a (40KD) [Pegasys®] one year post-treatment in patients with HBeAg-positive chronic hepatitis B. J Hepatol 2006;44(Suppl. 2):S23.
48. Marcellin P, Bonino F, Lau GKK, et al. The majority of patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40KD) [Pegasys®] sustain responses 2 years post-treatment. J Hepatol 2006;44(Suppl. 2):S275.