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Keywords:

  • chronic hepatitis B;
  • hepatitis B surface antigen;
  • hepatitis B virus;
  • hepatitis B e antigen;
  • pegylated interferon

Abstract

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References

Although chronic hepatitis B (CHB) is a global health threat, it is now a preventable and treatable disease. Seven agents have been approved for the treatment of CHB. Although many patients prefer potent long-term nucleos(t)ide analogues (NAs) as the first-line therapy because they are convenient to use and well-tolerated, a finite duration of pegylated interferon (PEG-IFN) is still an attractive strategy because it provides higher rates of off-therapy host immune control over hepatitis B virus (HBV) compared with NAs. In addition, the rates of HBeAg/HBsAg loss or seroconversion increase over time in patients who respond to PEG-IFN therapy. Nevertheless, these benefits are limited to 30% of all patients, and significant adverse effects are still a concern. Therefore, patients who can benefit most from PEG-IFN therapy should be more carefully selected according to baseline host and viral predictors, such as age, ALT level, viral load, HBV genotype and HBV mutants. In addition, on-treatment predictors including HBV DNA, HBeAg and HBsAg kinetics, can help decide who should continue or discontinue PEG-IFN and shift to NA. Understanding these factors can help determine personalized PEG-IFN therapy for CHB patients. In the near future, the treatment paradigm of CHB should be tailored on the basis of viral (HBV DNA level, HBV genotype and HBV mutants) and host (age, gender, ALT level and host genetic polymorphisms) factors, disease status (stage of fibrosis and comorbidities) and the selection of antiviral agents (immunomodulatory effect, antiviral potency, adverse effects and rate of drug resistance).

Abbreviations
ADV

adefovir dipivoxil

BCP

basal core promoter

CHB

chronic hepatitis B

CP

core promoter

ETV

entecavir

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

LAM

lamivudine

LdT

telbivudine

NAs

nucleos(t)ide analogues

PC

precore

PEG-IFN

pegylated interferon

SVR

sustained virological response

TDF

tenofovir disoproxil fumarate

Although safe and effective vaccines have been available for more than three decades, hepatitis B virus (HBV) infection remains an important public health problem and the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) worldwide. The long-term outcomes of chronic HBV infection vary widely. For example, the estimated annual incidence of cirrhosis is 2–6% for HBe antigen (HBeAg)-positive and 8–10% for HBeAg-negative patients. In addition, the estimated annual incidence of HCC is <1% for HBV carriers without cirrhosis and 2–3% for those with [1]. The lifetime risk of developing cirrhosis, liver failure or HCC in HBV carriers can be as high as 15–40% [2]. Therefore, effective antiviral agents to delay or stop the progression from chronic hepatitis to cirrhosis and HCC are urgently needed. The therapeutic endpoints for chronic hepatitis B (CHB) in the guidelines of the American Association for the Study of Liver Disease, the European Association for the Study of Liver and the Asian Pacific Association for the study of liver include sustained suppression of HBV replication, biochemical remission, histological improvement, HBeAg/HBsAg loss or seroconversion for HBeAg-positive patients, and ideally HBsAg loss or seroconversion for HBeAg-negative patients [3-5]. However, the ideal therapeutic endpoint of HBsAg seroclearance within a finite duration of therapy or the elimination of HBV is not obtained with current antiviral agents.

In clinical practice, patients with chronic HBV infection can be divided into asymptomatic carriers with no clinical evidence of liver injury and CHB patients with features of hepatitis activity. A recent update of the international management guidelines for CHB has suggested that treatment should be begun in CHB patients on the basis of serum HBV DNA levels, alanine aminotransferase (ALT) levels and/or histological severity [3-5]. In general, treatment criteria include abnormal ALT levels, HBV DNA above 2000–20 000 IU/ml and moderate/severe necroinflammation and/or significant fibrosis.

At present, two types of antiviral therapy are available for CHB: standard interferon (IFN) (α-2a and α-2b) or pegylated interferon α-2a (PEG-IFN α-2a) and five nucleos(t)ide analogues (NAs), including lamivudine (LAM), telbivudine, entecavir (ETV), adefovir dipivoxil and tenofovir disoproxil fumarate (TDF) [6]. The pharmacological properties of these two groups of drugs are different. IFN mainly has immune modulatory effects and weak direct antiviral effects, whereas NAs have direct antiviral effects only (Table 1). The clinical efficacy of these agents is summarized in Table 2. In this review, recent advances in the treatment of HBeAg-positive CHB with PEG-IFN will be summarized and discussed. In addition, the prediction of treatment response to PEG-IFN therapy will also be highlighted.

Table 1. Current treatment strategies for chronic hepatitis B
TreatmentaStrategyGoalDurationEfficacy
  1. a

    Pegylated interferon, entecavir and tenofovir are the preferred agents.

Standard or pegylated Interferon alfaSustained off-therapy response (immune control)Low HBV DNA level (<2000 IU/ml) and Normal ALT levelFiniteSustained response in ~30% of patients after 48 weeks of therapy, and may increase to 50% in those with good baseline and on-treatment factors
Nucleos(t)ide analogues (lamivudine, adefovir, telbivudine, entecavir or tenofovir)Maintained on-treatment response (viral control)Undetectable HBV DNA level and Normal ALTProlonged or indefiniteProfound suppression of HBV DNA with continued treatment without drug resistance
Table 2. Clinical efficacy of antiviral agents for HBeAg-positive chronic hepatitis B
EfficacyLamivudineAdefovirTelbivudineEntecavirTenofovirPegylated interferon
  1. a

    One year post 48 weeks of treatment.

  2. b

    Efficacy was assessed at 24 weeks after 48 weeks of treatment.

  3. c

    Two-year follow-up after 48 weeks of treatment.

  4. d

    Three-year follow-up after 48 weeks of treatment.

  5. NA, not available.

Log10 HBV DNA decline at 1 year5.543.56.456.96.44.5
HBV DNA undetectable (%) at 1 year36–4013–2160677625
ALT normalization (%) at 1 year60–7548–5477686839
Histologic improvement (%) at 1 year56–6253–6864.7727438a
HBeAg seroconversion (%) at
1 year18–21.512–1822.5212127b
2 year27NA29.631NA42c
3 year40NA46NA26NA
4 year47NANANA29NA
5 year6548NANANANA
HBsAg loss/seroconversion at
1 year10NA23.23–6b
2 year2.8NANA5.1NANA
3 yearNANANANA88d
4 year    10.8 

Pegylated interferon: an agent with dual immunomodulatory and antiviral effects

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References

Standard IFN was the first antiviral agent to be approved to treat CHB patients nearly 30 years ago. An early meta-analysis showed that standard IFN induced serum ALT normalization, loss of HBeAg, sustained suppression of serum HBV DNA measured by non-PCR assays and clearance of HBsAg by 25, 25, 23 and 6%, respectively, in HBeAg-positive patients [7]. In a long-term follow-up study for a median of 14 years, high HBsAg seroconversion was achieved (64%) in HBeAg-positive patients responding to standard IFN [8].

The half-life of polyethylene glycol (PEG) IFN is longer than standard IFN [9]. Two types of PEG-IFN have been developed: PEG-IFN α-2a (40 KD) and PEG-IFN α-2b (12 KD) [10]. In an early phase II study, the combined sustained virological response (SVR) (HBeAg loss, HBV DNA suppression and ALT normalization) of PEG-IFN α-2a was twice that with standard IFN α-2a (24% vs. 12%; P = 0.036) after 24 weeks off therapy [11].

In HBeAg-positive patients, two large international trials have shown that 1 year of PEG-IFN α-2a and PEG-IFN α-2b monotherapy resulted in HBeAg seroconversion in 32 and 29% of patients 6 months after the end of treatment, respectively. The virological response based on HBV DNA suppression was found to be modest with PEG-IFN. HBV DNA suppression to ≦400 copies/ml was only obtained in 14% of patients with PEG-IFN α-2a and 7% with PEG-IFN α-2b, respectively. However, HBsAg seroconversion was achieved in 3–5% of patients 6 months after the end of therapy [12, 13]. In an analysis of the long-term effects of PEG-IFN, 83% of 150 Asian HBeAg-positive patients treated with PEG-IFNα-2a for 48 weeks who achieved HBeAg seroconversion 6 months after treatment, had sustained seroconversion at 12 months. Furthermore, 38% of the patients who achieved HBeAg seroconversion 12 months post treatment had serum HBV DNA levels ≦400 copies/ml [14]. Moreover, long-term (mean follow-up of 3 years) sustained negative HBeAg and HBsAg in 172 European HBeAg-positive patients treated with PEG-IFN α-2b was 37 and 11%, respectively. In particular, sustained negative HBeAg and HBsAg was observed in 81 and 30% of 64 patients with an initial serologic response (HBeAg negativity after 26 weeks of treatment) [15]. Evidence suggests that PEG-IFN tends to be better than standard IFN for the treatment of CHB. The rate of HBsAg loss or seroconversion, the closest outcome to a cure of chronic HBV infection [16], increases over time in patients that respond to standard IFN and PEG-IFN.

Although antiviral treatment for CHB has significantly improved, most patients do not obtain HBsAg seroclearance, which is the ultimate goal of HBV therapy. Furthermore, relapse is common during post NA therapy follow-up. Therefore, combination therapy could be considered the ideal treatment for CHB [17]. One multicentre randomized controlled trial showed that PEG-IFN plus LAM resulted in greater on-treatment HBV DNA suppression than PEG-IFN monotherapy after 1-year (67% vs. 37%, P = 0.02). However, there was no difference in the SVR between the two treatment regimens (23% vs. 20%, P = 0.75) [18]. Whether the combination of a finite duration of PEG-IFN and an extended duration of potent NA such as ETV or TDF could be more effective is unclear. Our recent open-label, multicentre randomized controlled trial in 168 HBeAg-positive CHB patients showed that 24-week PEG-IFN plus ETV combination therapy followed by 120-week ETV monotherapy was safe but only resulted in a transient improvement in efficacy compared with 144-week ETV monotherapy. There was no difference in end-of-treatment virological and serological response rates between the two treatment arms [19]. Therefore, future studies are needed to clarify the best combination regimen with IFN.

Predictive factors of a response to pegylated interferon treatment

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References

Predictive factors of treatment response are important for the evaluation of treatment effectiveness in CHB patients. Several baseline viral factors have been identified to predict responses to PEG-IFN therapy (Table 3) [20].

Table 3. Hepatitis B viral factors associated with a favourable response to interferon therapy in chronic hepatitis B patients
 HBeAg-positiveHBeAg-negative
Baseline
Viral loadLowLow
Quantitative HBsAgNo correlationNo correlation
GenotypeA>D and B>CA>non-A
PC/BCP mutantsHigh mutant percentageControversial
On-treatment
HBV DNA declineNo correlation≥2 log10 IU/ml at week 12
Quantitative HBsAg decline<1500 IU/ml at week 12≥10% decline from baseline at week 12
Quantitative HBeAg decline<10 PEIU/ml at week 24 

Baseline viral predictors

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References

Viral load

Serum HBV DNA level is the best known predictor of an adverse clinical outcome (cirrhosis, HCC and death from liver disease) in adults with chronic HBV infection. Serum HBV DNA levels from <300 copies/ml (undetectable) to 1 million copies/ml or greater were found to represent a significant biological gradient of the risk of HCC [21, 22]. An earlier study of the literature using summative analysis also showed that pretreatment serum HBV DNA levels were significantly associated with the efficacy of IFN treatment including histological grading, serum ALT normalization and the incidence of HBeAg seroconversion [23]. Recent clinical trials have also confirmed that lower baseline HBV DNA levels were predictive of HBeAg loss or seroconversion in HBeAg-positive patients receiving PEG-IFN therapy [24, 25].

Quantitative HBsAg and HBeAg levels

Quantitative assays for serum HBsAg (qHBsAg) and HBeAg (qHBeAg) levels are available at present [26]. The relationship between qHBsAg, qHBeAg, intrahepatic HBV DNA and serum HBV DNA concentrations were recently analysed. In HBeAg-positive CHB patients, qHBsAg was positively correlated with intrahepatic HBV DNA and serum HBV DNA concentrations. In addition, qHBeAg was correlated with serum HBV DNA. On the contrary, there was a weak correlation between HBsAg and serum HBV DNA and no correlation with intrahepatic HBV DNA in HBeAg-negative CHB patients [27]. In relation to clinical phenotypes, HBsAg levels were much higher in HBeAg-positive patients in the immune tolerant and immune clearance phase than HBeAg-negative patients [28, 29]. These results show that there is a correlation between qHBsAg, qHBeAg and the progression of liver disease.

In two large international studies in patients receiving PEG-IFN α-2a, the baseline qHBsAg level was not correlated with the antiviral response, whatever the HBeAg status [30, 31]. qHBeAg levels were recently analysed in a clinical trial involving 271 HBeAg-positive patients who received PEG-IFN α-2a for 48 weeks. Results showed that the rate of HBeAg seroconversion decreased as pretreatment HBeAg levels increased. Patients with lower baseline qHBeAg levels had significantly higher rates of HBeAg seroconversion [32]. These results suggest that further studies are needed to validate the value of baseline qHBsAg and qHBeAg to predict responses to PEG-IFN therapy.

HBV genotype

At least 10 HBV genotypes (A to J) and several subtypes have been identified [33]. The impact of HBV genotype on the therapeutic response to IFN therapy has been recognized in several studies [34, 35]. In HBeAg-positive patients treated with standard IFN, the SVR defined as normalization of serum ALT levels and post-treatment HBeAg seroconversion is significantly better in genotype A and B patients than in genotype C and D patients [36]. A multicentre study on PEG-IFN in HBeAg-positive patients also showed that the rates of HBeAg seroclearance and sustained loss of HBeAg 3 years after the end of treatment were higher in genotypes A and B than in genotypes C and D. A long-term follow-up study in HBeAg-negative patients treated with PEG-IFN also showed that HBsAg seroclearance was significantly higher in genotype A (20%) than in genotypes B (6%), C (9%) and D (6%) patients [37]. A meta-analysis also confirmed that HBV genotype A patients respond better to IFN treatment than genotype D patients whatever the HBeAg status. Similarly, the response rate to IFN in HBeAg-positive genotype B patients is better than in genotype C patients [38]. Recently, pooled data from two large global trials in HBeAg-positive patients treated with PEG-IFN showed that genotype A patients with higher ALT levels or lower HBV DNA levels, as well as genotype B and C patients with both higher ALT levels and lower HBV DNA levels had a high probability of achieving a SVR. On the contrary, genotype D patients had the lowest chance of achieving a SVR, whatever the ALT or HBV DNA levels [39].

HBV mutants

Several common HBV mutant strains such as mutations in the precore (PC), core promoter (CP) and deletion mutations in the pre-S/S genes have been associated with progressive liver disease, including cirrhosis and HCC [2], thus their influence on HBV treatment requires further studies. A recent review showed that half of the studies in the literature suggested the PC G1896A mutation or the basal core promoter (BCP) A1762T/G1764A mutation were associated with the response to IFN therapy [40]. A recent study in 115 HBeAg-positive patients who received PEG-IFN α-2a for 6 months indicated that the BCP A1762T/G1764A mutation was associated with a combined response defined as HBeAg seroconversion, HBV DNA levels below 20 000 IU/mL as well as normalization of ALT 6 months after therapy had stopped (OR: 8.04, 95% CI: 2.00–32.28) [25]. We recently developed a new assay to accurately quantify the percentage of PC and BCP mutants with (PCR)-pyrosequencing and correlated the dynamic changes with IFN-induced HBeAg seroconversion in 203 HBeAg-positive patients. Multiple logistic regression analysis showed that the chance of HBeAg seroconversion increased by 2.2% (odds ratio [OR] = 1.022, 95% confidence interval [CI]: 1.009–1.034, P = 0.001) and 2.3% (OR = 1.023, 95% CI: 1.010–1.037, P = 0.001) per 1% increase in the percentage of pretreatment PC and BCP mutants, respectively, after adjustment for other predictors. However, only the pretreatment percentage of PC mutations was significantly associated with HBeAg seroconversion when HBV DNA <2000 IU/ml (OR = 1.030, 95% CI: 1.014–1.047, P < 0.001). Furthermore, the percentage of PC but not BCP mutations in patients achieving HBeAg seroclearance with HBV DNA <20 000 IU/mL increased significantly during IFN treatment (P = 0.039) [41].

On-treatment viral predictors

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References

Kinetics of quantitative HBsAg and HBeAg

Recently, the on-treatment kinetics or the decline in qHBsAg levels has been shown to be a useful predictor of response to antiviral treatment. In an international study, 1 year of PEG-IFN with or without LAM resulted in a significantly sustained decline in qHBsAg in HBeAg-positive patients. Patients with HBeAg loss and HBV DNA <10 000 copies/ml 26 weeks after the end of treatment had a significant decrease in qHBsAg compared with non-responders (decline at week 52: 3.3 vs. 0.7 log10 IU/ml, P < 0.001). Patients with no decline in qHBsAg at week 12 had a 97% probability of non-response and no chance of HBsAg loss at the end of follow-up [30]. Sonnoveld et al. further analysed 803 HBeAg-positive patients treated with PEG-IFN in three studies with available HBsAg. A stopping-rule based on an absence of decline from baseline was compared with a prediction-rule that used HBsAg levels of <1500 and >20 000 IU/ml to identify patients with high and low probabilities of response. These results showed that nearly all patients with HBsAg >20 000 IU/mL at week 24 failed to achieve a response, whatever the HBV genotype (Negative predictive value for response and HBsAg loss was 99 and 100%, respectively). Therefore, qHBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. Treatment discontinuation is indicated in all patients with HBsAg >20 000 IU/ml at week 24, whatever the HBV genotype [42]. Thus, on-treatment qHBsAg is useful not only to identify patients who are not likely to benefit from IFN as early as possible but also as a guide to the optimal treatment duration [43].

In addition to qHBsAg, a decline in qHBeAg has also been reported as a predictor of antiviral therapy [26]. In patients treated with 48 weeks of PEG-IFN, Fried et al. reported that more than half of the patients with a qHBeAg level <10 PEIU/ml at 24 weeks of treatment achieved HBeAg seroconversion 6 months after the end of treatment. In contrast, only 4% of patients with qHBeAg ≥100 PEIU/ml at 24 weeks of treatment achieved HBeAg seroconversion [32]. However, the commercial qHBeAg test is not yet available, and an on-treatment decline in qHBeAg as a predictor of treatment requires further studies for confirmation.

Host genetic variations

In addition to viral factors, host factors such as genetic variations are known to affect the natural course of patients with viral hepatitis [44]. In recent years, several host genetic variations such as HLA loci and IL28B gene polymorphisms have been reported to affect the clinical outcomes and treatment responses in patients with HCV or HBV infection [45-48]. However, there were very few studies investigating whether host genetic factors affect the response to IFN therapy in CHB patients. A previous study on HBeAg-positive patients who received PEG-IFN with or without LAM therapy showed that interleukin-1 beta -511 polymorphisms were associated with higher SVR (genotype C/T vs. C/C, adjusted odds ratio 10.4, 95% confidence interval: 1.1–96.9, P = 0.040) [49]. In addition, polymorphisms in IFN pathway genes were associated with a response to IFN treatment in CHB patients [50, 51]. A recent study in 115 HBeAg-positive CHB patients treated with PEG-IFN α-2a for 6 or 12 months suggested that the rs3077 G/G genotype at the HLA-DPA1 region was independently associated with a higher HBeAg seroconversion rate in HBeAg-positive patients 6 months after therapy had ended (OR: 3.49, 95% CI: 1.12–10.84) [25]. Although the IL28B genotypes have been shown to affect the SVR rate in patients with chronic hepatitis C, their role in CHB patients receiving IFN therapy remains controversial [52].

Although more evidence is required, these findings suggest that variations or polymorphisms of host immune response genes may play an important role in the response to treatment in CHB patients.

Conclusions

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References

Although many CHB patients prefer potent long-term NA therapy because it is convenient to use and well-tolerated, a finite duration of IFN is still an attractive strategy because it provides higher SVR rates (normal ALT levels with HBV DNA <2000 IU/ml and positivity of anti-HBe) than NAs. Moreover, the rates of HBeAg/HBsAg loss or seroconversion increase over time in patients that respond to IFN therapy. Nevertheless, these benefits are limited to 30% of all patients, and problems with tolerance remain a concern. Therefore, clinicians should select patients who can benefit most from IFN therapy based on baseline host and viral predictors, such as age, ALT level, viral load, HBV genotype and HBV mutants. In addition, on-treatment predictors including HBV DNA, HBeAg and HBsAg kinetics, can help decide who should continue or discontinue PEG-IFN therapy and shift to NA therapy. Moreover, host factors as well as virus-host interactions are known to be associated with IFN response. Understanding these factors can help determine personalized PEG-IFN therapy for CHB patients (Fig. 1). In the near future, the treatment paradigm of CHB should be tailored on the basis of viral (HBV DNA level, HBV genotype and HBV mutants) and host (age, gender, ALT level and host genetic polymorphisms) factors, disease status (stage of fibrosis and comorbidities) and the selection of antiviral agents (immunomodulatory effect, antiviral potency, adverse effects and rate of drug resistance) (Table 4). Finally, new agents with different mechanisms of action or new combination treatment strategies using baseline and on-treatment predictors could refine the CHB treatment algorithms in the next decade.

Table 4. Selection of HBeAg-positive chronic hepatitis B patients for interferon treatment
Younger age (short duration of infection)
Female gender with child bearing age
Compensated liver disease
Genotype A or B infection
Low HBV DNA level
High alanine aminotransferase (ALT) activity
Significant necroinflammatory activity
Mild fibrosis
Favourable single nucleotide polymorphisms (SNP) of host immune response genes
image

Figure 1. A hypothetical algorithm of personalized interferon therapy for chronic hepatitis B patients. This algorithm should be evaluated in future prospective clinical trials.

Download figure to PowerPoint

References

  1. Top of page
  2. Abstract
  3. Pegylated interferon: an agent with dual immunomodulatory and antiviral effects
  4. Predictive factors of a response to pegylated interferon treatment
  5. Baseline viral predictors
  6. On-treatment viral predictors
  7. Conclusions
  8. Disclosure
  9. References