SEARCH

SEARCH BY CITATION

Keywords:

  • analogues;
  • hepatitis B virus tools;
  • personalized medicine;
  • pegylated-IFN;
  • prediction;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References

Since its discovery by Blumberg in 1965, the hepatitis B virus antigen (HBsAg) is used as the fingerprint of hepatitis B infection. The HBsAg level is a reflection of the transcriptional activity of cccDNA. It is an important marker that not only indicates active hepatitis B infection but can also predict clinical and treatment outcomes. Assays for HBsAg quantification are fully automated and have high output. HBsAg titres are higher in HBe antigen (HBeAg)(+) than in HBeAg(−) patients and are negatively correlated with liver fibrosis in HBeAg(+) patients. In HBeAg(−) chronic hepatitis B, an HBsAg level <1000 IU/ml and an HBV DNA titre <2000 IU/ml accurately identify inactive carriers. During PEG-IFN treatment, HBsAg quantification is used to identify patients who will not benefit from therapy as early as week 12 on therapy, so that treatment may be stopped or switched- ‘week 12 stopping rule’. With nucleos(t)ide analogues (NA), the role of HBsAg quantification must be clarified. Several studies show that baseline and on-treatment HBsAg levels might identify patients that can be treated with no subsequent risk of reactivation. In clinical practice, HBsAg quantification is a simple and reproducible tool that can be used in association with HBV DNA to classify patients during the natural history of HBV and to monitor therapy.

Abbreviations
ETV

entecavir

HBV

hepatitis B virus

IFN

Interferon

NA

nucleos(t)ide analogues

NPV

negative predictive value

PEG-IFN

pegylated-IFN

PPV

positive predictive value

SVR

sustained virological response

TDF

tenofovir

The hepatitis B virus (HBV) is a small DNA virus. Upon entry into the cell, HBV sheds its protein coat and the partially double-strand genome is transported into the nucleus of the hepatocyte where it is transformed into a fully double-strand covalently closed circular DNA (cccDNA). The cccDNA resides in the nucleus of infected hepatocytes, where it acts as a template for transcription of the viral gene and recycles in the nucleus to renew the cccDNA pool [1, 2]. Viral proteins of clinical importance include the envelope protein (HBsAg) whose synthesis during the HBV viral life cycle is complex. HBsAg production exceeds that required for virion assembly, and excess surface envelope proteins are covalently linked and secreted as empty non-infectious filamentous or spherical sub-viral particles [3]. These empty particles may co-exist with anti-HBs as part of circulating immune complexes [4]. Serum HBsAg is a result of the combination of these proteins (complete virion, filamentous or spherical sub-viral particles). HBsAg quantification measures all three forms of systemic HBsAg.

Several studies have shown the relationship between intrahepatic markers of HBV infection (cccDNA and integrated HVB DNA) and serum HBsAg [3, 5-7]. Differences in HBsAg levels during the different phases of the disease reflect the distribution of cccDNA during the respective infection phases. HBsAg levels are higher in HbeAg-positive (+) than in HBeAg-negative (−) patients [6-8].

Clinical applications

HBsAg seroconversion (loss of HBsAg and development of anti-HBs) is rarely observed during the natural course of chronic HBV infection. The annual incidence is 1–2% world-wide [1]. It is the ultimate goal of therapy. Recently, quantitative serum HBsAg assays have been developed [9, 10], and the importance of HBsAg quantification has been recognized as an important marker to monitor the natural history in chronic hepatitis and predict treatment outcome [11-13]. HBsAg levels decrease more in patients receiving interferon (IFN), an immune modulator, than in those receiving nucleos(t)ides analogues (NA), potent inhibitors of HBV DNA replication [14].

Natural history

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References

HBeAg positive chronic hepatitis B

In the initial 2–3 decades of life, HBV infection is characterized by an immune tolerance phase in which patients usually have positive HBeAg, very high HBV DNA, normal ALT levels and minimal histological damage [14]. This is followed by an immune-clearance phase, which may lead to HBeAg seroconversion. Based on the results of cross-sectional studies, serum HBsAg levels were generally higher in patients in the immune tolerance phase than in the immune-clearance phase [3, 6-8, 13] (Fig. 1).

image

Figure 1. Serum HBsAg levels during natural history of hepatitis B virus infection. Median values with 95% CI. Adapted from Nguyen et al. [6]. Serum HBsAg levels are higher in HBeAg-postive (immune-tolerant and immune-clearance) than in HBeAg-negative chronic hepatitis B.

Download figure to PowerPoint

HBeAg negative chronic hepatitis B

Later in life, most of the HBV-infected population progresses to the immune active phase, loses HBeAg and seroconverts to anti-HBe (with various degrees of activity and fibrosis). Then, most of this HBeAg (−) chronic hepatitis B (CHB) population enters the inactive or low replicative phase, (characterized by wide fluctuations in serum HBV DNA levels and transaminases [15]. The clinical spectrum of HBeAg (−) CHB ranges from ‘inactive carrier’ status to aggressive HBeAg (−) CHB that is generally differentiated from ‘inactive carriers’ by serial serum ALT and HBV DNA level determinations [16, 17]. However, in 45–65% of cases, ALT activity can fluctuate with long periods of normal ALT levels, resulting in misclassification (Fig. 2). Inactive carriers have no or mild histological lesions in the liver with an excellent prognosis for survival and a low incidence of cirrhosis and HCC, while patients with HBeAg (−) CHB with fluctuating activity have a more severe disease progression with frequent cirrhosis [17-19]. Differentiating the latter from inactive carriers is highly important as these patients could benefit from therapy. According to NIH and EASL guidelines [20, 21], the differentiation between inactive and active phases of HBeAg (−) CHB is based on an HBV DNA cut-off of 2000 IU/ml. This cut-off has led to several controversial studies [17, 22-25].

image

Figure 2. Kinetics of HBsAg, HBV DNA and ALT follow-up during the natural history of a chronic hepatitis B-negative patient. This patient with ‘an inactive carrier’ pattern at inclusion shows several reactivation episodes, ALT >2N and dramatically increase in serum HBV DNA during the follow-up, while HBsAg level remained steady and above 3.3 log IU/ml.

Download figure to PowerPoint

Based on longitudinal studies, HBsAg levels are higher in patients with active HBeAg (−) CHB than in ‘inactive carriers’ [22-26].

A longitudinal Asian study in 68 HBeAg (−) CHB patients predominantly infected with genotype C reported that the patients with inactive disease tend to have lower HBsAg levels than those with active disease; 2.24 ± 1.61 log10 IU/ml vs. 2.98 ± 0.88 log10 IU/ml respectively (P = 0.054). No cut-off value can confidentially differentiate ‘inactive carriers’ [22]. During long-term follow-up (median 10 years), the authors report that HBsAg <1000 IU/ml predicts seroclearance (91% specificity: 75% sensitivity) [23]. A study performed by Brunetto et al. [24] in Italian genotype D patients reported that HBsAg levels are higher in patients with HBeAg (−) CHB than in ‘inactive carriers’ and that a single point quantification of HBV DNA <2000 IU/ml and HBsAg <1000 IU/ml identifies inactive carriers with a positive predictive value (PPV) of 88%. However, this observation must be validated across all HBV genotypes. Similar results were reported in a recent study from France [25] in 165 patients with HBeAg (−) CHB (genotypes A–E). HBsAg levels in this study were lower in the 76 ‘inactive carriers’ than in the 89 patients with an HBeAg (−) CHB; 3.25 ± 0.96 log10 IU/ml vs. 3.67 ± 0.70 log10 IU/ml respectively (P < 0.001). The combination of a single measurement of HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml identifies ‘inactive carriers’ with a PPV of 86%. More recently, the authors reported that the combination of a single measurement of HBsAg >1000 IU/ml and HBV DNA >200 IU/ml identifies patients with a ‘high risk of reactivation’ with a negative predictive value (NPV) of 96%, and sensitivity 92% [26]. The authors conclude that combination of HBsAg and HBV DNA levels at a single time point may accurately indentify HBeAg (−) CHB patients, during remission with a high probability of reactivation and who are good candidates for treatment.

HBsAg and liver histology

Seto et al. [27] found an association between higher HBsAg (≥25 000 IU/ml) serum levels and mild fibrosis (stage F ≤ 1) in a cohort of 140 Asian HBeAg (+) CHB patients (no indication of HBV genotype) with ALT ≤ 2 times the upper limit of normal. Similar results are reported in a cohort of 406 chronic hepatitis B patients with genotypes A–E [28]. A negative correlation was found between the level of HBsAg and the stage of fibrosis, so that patients with no or mild fibrosis (F 0–1 Metavir score) could be distinguished from those with moderate or severe fibrosis (≥ F2), in HBeAg (+) patients, with a high NPV (91%). Furthermore, the authors describe a specific serum HBsAg cut-off (3.85 log10 IU/ml) to identify moderate to severe fibrosis (≥ F2) in HBeAg (+) CHB patients infected with HBV genotypes B or C. This association was not observed in HBeAg (−) patients [28]. There was no association between HBsAg titre and histological grade found in either study.

HBsAg level and therapy

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References

Interferon therapy

Only a small proportion of patients (3–7%) experience HBsAg loss during 48 weeks of interferon-based (IFN) therapy [21]. The efficacy of pegylated-IFN (PEG-IFN) has been confirmed in two large pivotal studies [29, 30]. The HBeAg seroconversion rate was observed in 32% in HBeAg-positive patients [29] and an HBV DNA <400 IU/ml in 19% in HBeAg-negative patients [30]. In the early 1990's, HBsAg quantification was already considered to be a promising, simple and inexpensive method to monitor viral replication in chronic hepatitis B patients who were receiving IFN treatment [31]. More recently, the availability of well-standardized commercial assays has renewed interest in the quantitative serum HBsAg as a biomarker for treatment response in chronic hepatitis B [9, 10].

HBeAg-positive patients

Current data [32-37] indicate that on-treatment HBsAg quantification could help identify either patients with a high probability of sustained virological response (SVR) or non-responders. In a study by Chan et al. [32], SVR rates were 62 and 11% in patients with HBsAg ≤300 IU/ml and in those with HBsAg >300 IU/ml at 24 weeks of therapy respectively. The authors also showed that patients with a combined response of HBsAg ≤300 IU/ml and a decrease of ≥1 log10 IU/ml at 24 weeks had higher SVR rates than those without the combined response (75% vs. 15%), with a PPV and NPV of 75 and 85% respectively. Tangkijvanich et al. [33] report that baseline HBsAg levels were lower in patients with HBeAg seroconversion at the end of therapy than in non-responders. In the NEPTUNE study [35, 37] the highest HBeAg seroconversion rates were observed in patients with HBsAg levels ≤ 1500 IU/ml at 12 or 24 weeks of therapy with a PPV of 57 or 54% and a NPV of 72 or 76% respectively. These results confirm those of the phase III PEG-IFN alpha 2a treatment registration trial on [34]. Sonneveld et al. [36] showed that patients who received a combination of PEG-IFN plus lamivudine had a more pronounced on-treatment decrease in HBsAg patients than those who received PEG-IFN alone, although the former relapsed. The absence of decline at week 12 had a NPV of 97% for SVR and no chance of HBsAg loss. The phase III registration trial [34] by Lau et al. reported a lower NPV (82%) than the study by Sonneveld et al. The discrepancies between the two studies [34, 36] might be owing to the different populations studied. Indeed, in the study by Sonneveld et al., most of the patients had genotypes A and D, whereas the Lau study included genotypes B and C Asian patients. It is interesting to note that certain studies have reported a more significant decrease in HBsAg and more frequent HBsAg in patients with HBV genotype A who receive PEG-IFN [38-40].

HBeAg-negative patients

The response rate to PEG-IFN is low (<20%) in HBeAg (−) patients [41-44]. These patients are difficult to monitor. Indeed, most of them achieve undetectable serum HBV DNA at the end of therapy, but relapse after treatment is stopped [30, 43, 44]. Therefore, predictive factors of on-treatment response may help define more appropriate treatment strategies in certain patients. The most recent evidence suggests that HBsAg quantification is a worthwhile marker for monitoring PEG-IFN therapy [45-47] (Fig. 3).

image

Figure 3. Changes in serum HBV DNA (A) and HBsAg (B), during PEG-IFN therapy. Illustration of HBV DNA and HBsAg kinetics in sustained responder (solid line) and relapser (dash line) during peginterferon therapy. Adapted from Moucari et al. [45]. Serum HBV DNA was undetectable at the end of therapy (A) in both patients with sustained virological response and with relapse. During therapy, HBsAg decreased (B) only in patients who developed sustained virological response.

Download figure to PowerPoint

Rijckborst et al. [43] reported that the combination of HBsAg and a decrease in HBVDNA is the best predictor of an SVR in patients receiving PEG-IFN. A lack of decrease in HBsAg and a serum HBVDNA decline of less than 2 log10 IU/ml have a NPV of 100% for SVR. Another [45] study has shown that a serum HBsAg decrease of ≥ 0.5 log IU/ml at week 12 had a high PPV of SVR (PPV 89%) and a lack of decrease of ≥1 log10 IU/ml at week 24 had a high NPV of non-SVR (NPV 92%).

Studies have investigated end- and post-treatment HBsAg titres to predict SVR and loss of HBsAg during post-treatment follow-up. In a cohort of 127 HBeAg-negative genotype D patients who received 48 weeks of PEG-IFN treatment, Brunetto et al. [46] showed that an on-treatment ≥1 log10 IU/ml HBsAg decrease and an HBsAg level <10 IU/ml at the end of therapy were highly predictive for a SVR at the 24-week post-treatment follow-up and for HBsAg loss at the 3-year post-treatment follow-up. In this study, at the 3-year post-treatment follow-up, an HBsAg loss was observed in 52% of the patients with an HBsAg <10 IU/ml at week 48 of treatment, compared with only 2% of the patients with an HBsAg>10 IU/ml at week 48. The authors did not find any association between serum HBV DNA response (<400 IU/ml) at the end of therapy and HBsAg loss. A French retrospective study [48] also reported that most of the patients who lost HBsAg during post-treatment follow-up had a ≥1 log10 IU/ml decrease in HBsAg levels at the end of 48 weeks of IFN treatment followed by a steady decrease until seroclearance.

Week 12 stopping rule

Most studies report that the absence of a decrease in HBsAg or a HBV DNA decline of < 2 log10 after 12–24 weeks of a 48-week course of PEG-IFN is associated with a NPV of 84–100% for SVR [49] (Table 1). Rijckborst et al. [50] confirmed these results in patients in the PARC study [51] and performed external validation in the phase III registration study [28] and the PegBeLiver study [51], both of which included patients with HBV genotypes A–D. There was a NPV ≥95% for SVR in both validation studies in the absence of a decrease in HBsAg or a decline in HBV DNA <2 log10 IU/ml at week 12 of treatment. The authors propose a response-guided therapy algorithm based on HBsAg kinetics at week 12 of treatment. Early identification of non-responders would allow discontinuation of therapy and/or changing the treatment strategy (Table 1).

Table 1. Sustained virological response (SVR) as predicted by serum HBsAg at week 12 and 24 of treatment
 SVR WeekNPV Week
AuthorsHBeAgHBsAg (IU/ml)12241224
  1. a

    Not available.

  2. b

    Associated with < 2 log decrease in HBV DNA from baseline.

Chan [32]Positive< 300naa62%naanaa
  > 1 log declinenaa75%naa85%
Lau [34]Positive> 20 00016%15%naaNaa
  < 150057%54%72%76%
GanePositive> 20 0000%0%84%naa
  < 150058%%57%naanaa
Sonneveld [36]PositiveNo decline3%8%97%naa
Piratvisuth [37]PositiveNo decline18%naa82%naa
Piratvisuth [52]Positive< 150057%naa naa
Liaw [53]Positive< 150057%54%84%85%
  >20 0000%0%100%100%
Ma [54]Positive<150033%naa91%naa
  <2890naa43%naa95%
Rijckborst [43]NegativeDecline Yesb39%naanaanaa
  decline Nob24%naa100%naa
Moucari [45]Negative<0.5 log decline88%92%90%97%
Rijckborst [50]NegativeNo declineb0%–5%naa95–100%naa
Lampertico [55]Negative≤7500naa17%naanaa
  >7500naa7%naanaa
Brunetto [56]Negative≥ 10 decline47%43%naanaa
  <10 decline16%13%naanaa

Nucleos(t)ides analogues

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References

The treatment paradigm for HBV has shifted in the past decade from a finite duration of treatment with IFN to long-term HBV suppression with nucleos(t)ides analogues (NA). Indeed, the newer agents such as tenofovir or entecavir are more effective in suppressing HBV and are less likely to be associated with drug resistance than original NA. In addition, they are orally administered and have excellent safety profile. However, they must probably be taken indefinitely because withdrawal is generally associated with viral reactivation, and HBsAg seroconversion is rarely reported. Although HBVDNA becomes rapidly undetectable, studies have clearly shown that the decline in HBsAg titres is significantly lower with NA therapy than with IFN-based treatment [57, 58] (Fig. 4). Several studies have reported that baseline HBsAg levels and on-treatment HBsAg quantification are good predictive markers of the end of treatment response and SVR [57-66]. Zoutendijk et al. [67] investigated HBsAg kinetics in patients who were successfully treated with long-term entecavir (ETV) or tenofovir (TDF). The authors used linear mixed regression analysis of individual HBsAg declines to estimate the duration of therapy required to achieve an HBsAg decline of 1 log10 UI/ml from baseline and HBsAg clearance. They showed that the median durations of therapy to achieve a 1 log10 IU/ml decrease were as follows: 6.6 [1.7–18] years and 8 [0.5–15] years in HBeAg (+) and HBeAg (−) patients respectively. Median durations for HBsAg clearance were as follows: 36 [10–93] years and 39 [1.3–90] years in HBeAg (+) and HBeAg (−) patients respectively. These results show the importance of determining HBsAg cut-offs to discontinue NA therapy with lowest risk of reactivation.

image

Figure 4. Changes in HBsAg levels in HBeAg-positive and HBeAg-negative patients during PEG-IFN or Entecavir therapy. Mean changes compared with baseline for HBsAg titres in patients receiving either peginterferon or entecavir therapy. Adapted from Reijinders et al. [58]. The kinetics shows sharper decrease in patients receiving peginteferon therapy than in patients receiving entecavir therapy independently from AgHBe status. Similar results are reported in HBeAg-negative chronic hepatitis B patients receiving either interferon or lamivudine [57].

Download figure to PowerPoint

In the two pivotal studies of TDF [68, 69], study 102 (HBeAg −) and study 103 (HBeAg +) patients, the authors confirm that HBsAg kinetics is deeper in HBeAg (+) patients than in HBeAg (−) and in patients receiving TDF monotherapy. The only patients with HBsAg loss were HBeAg (+) patients with a ≥2 log10 IU/ml HBsAg decrease from baseline at 24 weeks of therapy, a higher baseline HBsAg level and genotypes A or D. In a cohort of 162 HBeAg (+) patients with HBV DNA <60 IU/ml after 3 years of telbuvidine therapy, Wursthorn et al. [62] showed that 25% of patients with ≥1 log10 IU/ml HBsAg decrease after 1 year of therapy had an HBsAg loss compared with 1.4% of patients with <1log10 IU/ml HBsAg decrease. The study by Reijnders et al. [58] in HBeAg (+) or (−) patients, who received 48 weeks of either PEG-IFN or ETV, an HBsAg decline was only observed in HBeAg (+) patients after 48 weeks of either PEG-IFN or ETV therapy. In HBeAg (−) patients, no decline in HBsAg levels was observed in patients receiving ETV. Recent studies including treatment-naive patients receiving NA report that low baseline HBsAg levels and an early decline in HBsAg (24-week therapy) are good predictors of SVR [63-66]. Furthermore, studies suggest that an HBsAg cut-off ≤2–3 log10 IU/ml could be used for treatment discontinuation [70-73]. In the study by Liang et al. [70], 121 consecutive patients were prospectively recruited after treatment was stopped (lamivudine, adefovir, entecavir). The authors report that higher HBsAg levels at the end of treatment were associated with higher risk of relapse. End of the treatment, HBsAg levels ≤ 3 log10 IU/ml and ≤ 2 log10 IU/ml were associated with a 31 and 9% relapse respectively. Similar results are reported by Cai et al. [73] in patients receiving 2 years of telbuvidine therapy. An HBsAg level ≤2 IU/ml at the end of treatment cessation had a PPV and NPV for the prediction of SVR of 100 and 93% respectively.

Recently, it has been proposed that in HBe negative-patients the combination of HBsAg level < 1000 IU/ml and HBV DNA < 2000 IU/ml can be considered as a probable criteria to define the minimal risk for hepato-cellular carcinoma (74).

Conclusions

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References

Recent studies on serum HBsAg monitoring show that HBsAg levels change during the natural course of chronic hepatitis B and during ongoing therapy. These results can be used to determine the best management strategy for patients. During the natural history of HBV, HBsAg quantification can be used to differentiate between inactive carriers (no need for treatment) and HBeAg (−) chronic hepatitis B patients, who are likely to reactivate (closer monitoring) and who can benefit from therapy. During PEG-IFN therapy, early HBsAg monitoring could be used to develop a response-guided algorithm: to stop or switch therapy at week 12 in poor responders, to continue standard 48-week treatment in most patients with a favourable response and to extend therapy for intermediate on-treatment responders to improve the chances of response. The role of HBsAg monitoring during NA therapy must be clarified. The development of stopping rules should be determined in these life-long therapies. Several studies suggest that baseline and on-treatment HBsAg levels might help identify patients who can stop therapy with no risk of reactivation.

Disclosure

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and Merck. Patrick Marcellin is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and Merck.

The rest of the authors have no disclosure.

References

  1. Top of page
  2. Abstract
  3. Natural history
  4. HBsAg level and therapy
  5. Nucleos(t)ides analogues
  6. Conclusions
  7. Disclosure
  8. References
  • 1
    Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004; 350: 11829.
  • 2
    McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009; 49: S4555.
  • 3
    Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004; 126: 17508.
  • 4
    Madalinski K, Burczynska B, Heermann KH, et al. Analysis of viral proteins in circulating immune complexes from chronic carriers of hepatitis B virus. Clin Exp Immunol 1991; 84: 493500.
  • 5
    Chan HL, Wong VW, Tse AM, et al. Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response. Clin Gastroenterol Hepatol 2007; 5: 14628.
  • 6
    Nguyen T, Thompson AJ, Bowden S, et al. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol 2010; 52: 50813.
  • 7
    Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51: 193344.
  • 8
    Jaroszewicz J, Calle Serrano B, Wursthorn K, et al. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective. J Hepatol 2010; 52: 51422.
  • 9
    Wursthorn K, Jaroszewicz J, Zacher BJ, et al. Correlation between the Elecsys HBsAg II assay and the architect assay for quantification of hepatitis B surface antigen (HBsAg) in serum. J Clin Virol 2011; 50: 2926.
  • 10
    Sonneveld MJ, Rijckborst V, Boucher CAB, et al. A comparison of two assays for quantification of hepatitis B surface antigen in patients with chronic hepatitis B. J Clin Virol 2011; 51: 1758.
  • 11
    Liaw YF. Clinical utility of hepatitis B surface antigen quantification in patients with chronic hepatitis B: a review. Hepatology 2011; 53: 21219.
  • 12
    Chan HL, Wong GL, Wong VW. A review of the natural history of chronic hepatitis B in the era of transient elastography. Antivir Ther 2009; 14: 48999.
  • 13
    Martinot-Peignoux M, Lapalus M, Lada O, et al. Natural history of hepatitis B (HBV) infection: role of HBV genotype (A to E) assessed in a large cohort. Hepatology 2011; 54(Suppl): 609A.
  • 14
    Chan HL, Thompson A, Martinot-Peignoux M, et al. Hepatitis B surface antigen quantification: why and how to use it in 2011-A core group report. J Hepatol 2011; 55: 112131.
  • 15
    Brunetto MR, Oliveri F, Rocca G, et al. Natural course and response to interferon of chronic hepatitis B accompaned by antibody to hepatitis B e antigen. Hepatology 1989; 10: 198202.
  • 16
    Sung JJ, Chan HL, Wong ML, et al. Relationship of clinical and virological factors with hepatitis activity in hepatitis B e antigen-negative chronic hepatitis B virus-infected patients. J Viral Hepatol 2002; 9: 22934.
  • 17
    Martinot-Peignoux M, Boyer N, Colombat M, et al. Serum hepatitis B virus HBV DNA levels and liver histology in inactive HBsAg carriers. J Hepatol 2002; 36: 5436.
  • 18
    Brunetto MR, Oiveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon and untreated patients: a long term cohort study. J Hepatol 2002; 36: 26370.
  • 19
    Papatheodoridis GV, Manesis EK, Manalakopoulos S, et al. Is there a meaninful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B infection? Hepatology 2008; 48: 14519.
  • 20
    Lok As, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000-summary of a workshop. Gastroenterology 2001; 120: 182853.
  • 21
    EASL clinical practice guidelines: management of chronic hepatitis B. European Association for the Study of the Liver. J Hepatol 2012; 50: 22742.
  • 22
    Chan HL, Wong VW, Wong GL, et al. A longitudinal study on the natural history of serum HBsAg changes in chronic hepatitis B. Hepatology 2010; 52: 123241.
  • 23
    Chan HL, Wong GL, Tse CH, et al. Definition of inactive hepatitis B carrer by serum HBsAg and HBV DNA levels – a long-term follow-up study on HBsAg seroclearance. J Hepatol 2011; 54: S144.
  • 24
    Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010; 139: 48390.
  • 25
    Martinot-Peignoux M, Lada O, Cardoso AC, et al. Quantitative HBsAg: a new specific marker for the diagnosis of HBsAg inactive carriage. Hepatology 2010; 52: 992A.
  • 26
    Martinot-Peignoux M, Lapalus M, Laouénan C, et al. How to distinguish HBeAg negative chronic hepatitis B, with high risk of reactivation, from inactive carriers: is there a place for HBsAg quantification? Hepatology 2012; 56(Suppl): 434A.
  • 27
    Seto WK, Wnog DKH, Fung J, et al. High hepatitis B surface antigen levels predict insignificant fibrosis in hepatitis B e antigen positive chronic hepatitis B. PLoS ONE 2012; 7: e43087.
  • 28
    Martinot-Peignoux M, Carvalho RJ, Cardoso AC, et al. Significant genotype-specific association of hepatitis B surface antigen level and severity of liver disease in patients with chronic hepatitis B. Hepatology 2011; 54(Suppl): 1078A.
  • 29
    Lau GKK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamuvidine, and the combination for HbeAg-positive chronic hepatitis B. N Engl J Med 2005; 352: 268295.
  • 30
    Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a, lamuvidine, and the two in combination for HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 120617.
  • 31
    Janssen HLA, Kerhof-Los CJ, Heijtink RA, Schalm SW. Measurement of HBsAg to monitor hepatitis B viral replication in patients on α-interferon therapy. Antivir Res 1994; 23: 2517.
  • 32
    Chan HL, Wong VW, Chim AM, et al. Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B. Aliment Pharmacol Ther 2010; 32: 132315.
  • 33
    Tangkijvanich P, Komolmit P, Mahachai V, et al. Low pretreatment serum HBsAg level and viral mutations as predictors of response to peginterferon alfa-2b therapy in chronic hepatitis B. J Clin Virol 2009; 46: 11723.
  • 34
    Lau G, Marcellin P, Brunetto M. On treatment monitoring of HBsAg levels to predict response to peginterferon alfa-2a in patients with HBeAg-positive chronic hepatitis B. J Hepatol 2009; 50: S333.
  • 35
    Gane E, Jia J, Han K, et al. NEPTUNE study; on treatment HBs Ag level analysis confirms prediction of response observed in phase 3 study of peginterferon alfa-2a in HBeAg positive patients. J Hepatol. 2011; 54: S2544. Abstract 69
  • 36
    Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 2010; 52: 12517.
  • 37
    Piratvisuth T, Marcellin P. Further analysis is required to identify an early stopping rule for peginterferon therapy that is valid for all HBeAg-positive patients. Hepatology 2011; 53: 10545.
  • 38
    Flink HJ, van Zonneveld M, Hansen B, et al. treatment with Peg-Interferon a-2a for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype? Am J Gastroenterol 2006; 101: 297303.
    Direct Link:
  • 39
    Soneveld MJ, Rijckborst V, Cakalog-1 lu Y, et al. Durable hepatitis surface antigen decline in hepatitis B e antigen positive chronic hepatitis B patients treated with pegylated interferon-a2b: relation to response and HBV genotype. Antiviral Ther 2012; 17: 917.
  • 40
    Moucari R, Martinot-Peignoux M, Mackiewicz V, et al. Influence of genotype on hepatitis B surafce antigen in hepatitis B e antigen-negative patients trated with pegylated interferon-a2a. Antiviral Ther 2009; 14: 11838.
  • 41
    Hadziyannis SJ. Treatment paradigms on hepatitis Be antigen-negative chronic hepatitis B patients. Expert Opin Investig Drugs 2007; 16: 77786.
  • 42
    Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007; 56: 699705.
  • 43
    Rijckborst V, Hansen BE, Cakalog-1 lu Y, et al. Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology 2010; 52: 45461.
  • 44
    Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology 2009; 136: 216979.
  • 45
    Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 2009; 49: 11517.
  • 46
    Brunetto MR, Moriconi F, Bononi F, et al. Hepatitis B virus surface antigen levels: a guide to sutained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009; 49: 114150.
  • 47
    Moucari R. Peginterferon for chronic hepatitis B: predicting success with on-treatment benchmarks. J Gastroenterol Hepatol 2010; 25: 14745.
  • 48
    Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol 2009; 50: 108492.
  • 49
    Lampertico P, Liaw YF. New perspectives in the therapy of chronic hepatitis B. Gut 2012; 61(Suppl. 1): i1824.
  • 50
    Rijckborst V, Hansen BE, Ferenci P, et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alpha-2a. J Hepatol 2012; 6: 100611.
  • 51
    Lampertico P, Vigano P, Di Costanzo g, et al. Extended (2 years) treatment with peginterferon alfa-2a improves sustained response rates in genotype D patients with HBeAg negative chronic hepatitis B. J Hepatol 2010; 52: S45.
  • 52
    Piratvisuth T, Lau GKK, Marvellin P, et al. On-treatment decline in serum HBsAg levels predicts sustained immune control and HBsAg clearance 6 month post-treatment in HBsAg positive hepatitisB virus-infected patients treated with peginterferon alfa-2a (40kD) (PEGASYS). Hepatol Int 2010; 4: 152.
  • 53
    Liaw YF, Jia JD, Chan HLY, et al. Shorter duration and lower doses of peginterferon alfa-2a are associated with inferior hepatitis Be antigen seroconversion rates in hepatitis B virus genotypes B or C. Hepatology 2011; 54: 15919.
  • 54
    Ma H, Yang RF, Wei L. Quantitative serum HBsAg and HBaAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa 2b in HbeAg positive patients. JGH 2010; 25: 1498506.
  • 55
    Lampertico P, Vigano M, Di Costanzo GC, et al. Response-guided peginterferon alfa-2a therapy based on HBsAg levels at week 12 and week 24 or 48 improves respose rates in HBeAg negative genotype D patients. J Hepatol 2011; 56: S207.
  • 56
    Brunetto M, Bonino F, Marcellin P, et al. Kinetics of HBsAg decline in patients with HBeAg negative chronic hepatitis B treated with peginterferon alfa 2a according to genotype and its association woth sustained HBsAg clearance. Hepatology 2008; 48(Suppl): 740A.
  • 57
    Manesis EK, Hadziyannis ES, Angelopoulou OS, Hadziyannis SJ. Prediction of treatment-related HBsAg loss in HBeAg-negative chronic hepatitis B: a clue from serum HBsAg levels. Antivir Ther 2007; 12: 7382.
  • 58
    Reijnders JG, Rijckborst V, Sonneveld MJ, et al. Kinetics of hepatits B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol 2011; 54: 44954.
  • 59
    Lee MH, Lee DM, Kim SS, et al. Correlation of serum hepatitis B srface antigen level with response to entecavir in naive patients with chronic hepatitis B. J Med Virol 2011; 83: 117886.
  • 60
    Lee JM, Ahn SH, Kim HS, et al. Quantitative hepatitis B surface antigen and hepatitis B e atigen titers in prediction of treatment response to entecavir. Hepatology 2100; 53: 148693.
  • 61
    Chen J, Wang Z, Zhou B, et al. Factors associated with hepatitis B surface antigen levels and its on-treatment changes in patients under lamivudine therapy. Antiviral ther 2012; 17: 719.
  • 62
    Wursthorn K, Jung M, Riva A, et al. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology 2010; 52: 161120.
  • 63
    Gramenzi A, Log-1 gi E, Micco L, et al. Serum hepatitis B surface antigen monitiring in long-term lamuvudine-treated hepatitis B virus patients. J Viral Hepatitis 2011; 10: 46874.
  • 64
    Zoulim F, Carosi G, Greenbloom S, et al. Quantification of HBsAg in nucleos(t)ides-naive patients treated for chronic hepatitis B with entecavir or entecavir plus tenofovir in the BE-LOW study. J Viral Hepatitis 2012; 19(Suppl. S3): O224.
  • 65
    Bruce MJ, Horner M, Knighton S, et al. Strong decline in HBsAg levels after virological response in a large monocentric therapy cohort: potential to select HBeAg positive chronic hepatitis B patients for finite duration? Hepatology 2012; 56(Suppl): 439A.
  • 66
    Orito E, Kusakabe A, Kanie H, et al. Quantification of HBsAg predicts response to naive entrcavir therapy in chronic hepatitis B patients with genotype C. Hepatology 2012; 56(Suppl): 395A.
  • 67
    Zoutendijk R, Hansen BE, Van Vuuren AJ, Boucher CA, Janssen HL. Prediction of HBsAg loss using HBsAg decline after long-term virological response to nucleos(t)ide analogue therapy for chronic hepatitis B. Hepatology 2010; (Suppl): 509A.
  • 68
    Marcellin M, Heathcote EJ, Buti M, et al. Tenofovir disiproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008; 359: 244255.
  • 69
    Heathcote EJ, Marcellin M, Buti M, et al. Three years efficacy and safety of tenofovir disiproxil fumarate treatment for chronic hepatitis B. Gastroenterrology 2011; 140: 13243.
  • 70
    Liang Y, Jiang J, Su M, et al. Predictors of relapse in chronic hepatitis B after discontinuation of antiviral therapy. Aliment Pharmacol Ther 2011; 34: 34452.
  • 71
    Petersen J, Buggischi P, Stoehr A, et al. Stopping long-term nucleos(t)ides analogue therapy before HBsAg loss or seroconversion in HBeAg negative CHB patients: experience from five referral centers in Germany. Hepatology 2011; 54(Suppl): 1417A.
  • 72
    Suh SJ, Yeon JE, Yoon EL, et al. Quantification of serum hepatitis B surface antigen as a predictor of off-treatment sustained virological response in in chronic hepatitis B patients treated with oral nucleos(t)ide analogue. J Hepatol 2012; 56(Suppl): S71S204.
  • 73
    Cai W, Xie Q, An B, et al. On-treatment serum HBsAg level is predictive of sustained off-treatment virologic response to telbivudine in HBeAg-positive chronic hepatitis B patients. J Clin Virol 2010; 48: 226.
  • 74
    Tseng TC, Liv CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012; 142: 11409.