SEARCH

SEARCH BY CITATION

Chronic hepatitis B (CHB) is an immune-based disorder in which the extent of disease as well as the frequency and quality of virologic response are profoundly influenced by the strength of the host immunologic response.1 Therefore, all of the international practice guidelines advocate interferon or peginterferon as potential first-line therapy for both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients.2,3 This is based on the immunomodulatory properties of peginterferon, and its efficacy to restore the host immune control on hepatitis B virus (HBV) replication, resulting in sustained disease remission in a proportion of patients after a finite course of therapy.4–7 This is emphasized by the imperfect association between the profound suppression of HBV DNA and the low rate of HBeAg and hepatitis B surface antigen (HBsAg) seroclearance observed in patients treated with nucleos(t)ides analogs (NUC).8

Nonetheless, the use of peginterferon currently accounts for no more than 10% of all prescriptions for CHB treatment in the USA and Europe, and the usage is probably to be even less in Asia. A major hindrance to its wide application is its lack of effectiveness in a large proportion of patients.9 In this respect, international practice guidelines do not specifically advocate its use as being preferred in specific subsets of patients who are most likely to have a sustained virologic response (SVR) and HBeAg/HBsAg seroconversion. Previous studies have tried to circumvent this shortcoming to a certain extent by the use of response predictor models based on pre-treatment host and viral factors such as age, gender, serum alanine aminotransferase (ALT) level, serum HBV DNA level, and HBV genotype. All of these parameters have been independently associated with SVR in multivariate analyses.10,11 However, their predictive values (odds ratio) were not powerful. Therefore, the use of these pre-treatment parameters to decide which treatment regimen to start (peginterferon versus NUC) may be somehow questionable. These data highlight the urgent need for more accurate predictors that allow the selection of patients who will likely benefit from a finite course of peginterferon or, alternatively, will determine whether extensive or indefinite treatment with a nucleos(t)ide analog is likely to be a better option.

Regardless of patient baseline characteristics, it is also worthwhile for physicians to determine in the early phase of treatment with peginterferon, which patient is less likely to develop SVR and should thus discontinue or consider alternative treatments (‘stopping rule’). An example of the usefulness of such a ‘stopping rule’ has been found in the treatment of hepatitis C virus (HCV). The use of on-treatment HCV RNA measurements in the early phases of treatment (rapid and early virological responses) is highly predictive of SVR. However, in HBV-infected patients, the relationship between HBV DNA and HBeAg/HBsAg is not as straightforward, because, as already mentioned, seroconversion does not necessarily occur even though HBV DNA is markedly suppressed. Therefore, it seems logical to evaluate HBeAg and HBsAg as direct predictors of seroconversion and SVR.

A number of recent studies have suggested that achieving specific virological benchmarks during treatment can be helpful in predicting SVR and HBsAg clearance.12 One of the more unique interesting associations has been with serum HBsAg concentration during treatment. In a recent study of 48 patients with HBeAg-negative chronic hepatitis B treated with peginterferon for 48 weeks, early serological response defined as early HBsAg decline during treatment was highly predictive of SVR (defined as undetectable HBV DNA by PCR 24 weeks after treatment). A drop of at least 0.5 log10 and 1 log10 IU/mL in serum HBsAg concentration at treatment weeks 12 and 24, respectively, had negative predictive values (NPV) of 92% and 97% for SVR.13 Of note, the kinetics of HBV DNA decline throughout treatment were nearly identical for sustained responders and relapsers but were quite different when HBsAg decline was assessed, suggesting that measurement of HBsAg concentration may more reliably distinguish those destined to have an SVR.13

In this issue of JGH, Wei et al. demonstrate that quantification of HBsAg and HBeAg in serum may be also a useful assay to evaluate the sustained response (HBeAg seroconversion) in HBeAg-positive patients treated with peginterferon.14 The authors were able to distinguish patients who did not develop SVR as early as treatment week 12 (NPV = 92% and 95% for HBsAg and HBeAg cut-offs, respectively). Interestingly NPV was 100% for both markers when assessed at treatment week 24.

Recently, data were analyzed from a large, randomized, multinational phase III registration trial involving 271 HBV-infected HBeAg-positive patients who received peginterferon alfa-2a for 48 weeks. On-treatment serum HBeAg levels used as a quantitative tool to predict SVR in this study, showed similar high NPV at weeks 12 and 24 of therapy. Quantifying HBeAg during therapy in this study also allowed the demarcation of late responders from nonresponders, a subgroup of patients who were not differentiated by changes in HBV DNA levels.15

Nonetheless, the study by Wei et al. remains the first study to date to address the application of HBsAg quantification for the prediction of SVR to peginterferon in HBeAg-positive patients. This is important given the absence of a commercially available assay for quantifying HBeAg, leading to the use of ‘in-house’ assays in these studies. By contrast, a chemilumiscent standardized immunoassay, the Abbott Architect HBsAg QT assay is available for HBsAg quantification. This is a two-step immunoassay, based on a chemiluminescent microparticle immunoassay (CMIA) technology which uses microparticles coated with monoclonal anti-HBs for the quantitative determination of HBsAg in serum and plasma. In the first step, sample and anti-HBs coated paramagnetic microparticles are combined. HBsAg present in the sample binds to the anti-HBs coated microparticles. After washing, acridinium-labeled anti-HBs conjugate is added in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs). A direct relationship exists between the amount of HBsAg in the sample and the RLUs detected by the Architect optical system. The concentration of HBsAg in the specimen is determined using a previously generated Architect HBsAg calibration curve. This standardized assay presents a detection threshold of 0.05 International Units (IU)/mL and a quantification dynamic range of nearly 4 log10 magnitude (from 0.05 to 250 IU/mL). The HBsAg quantification is obtained from a calibration curve established against the 1st HBsAg World Health Organization (WHO). To extend this quantification range up to 125 000 IU/mL, 20-fold and 500-fold dilutions using the Architect HBsAg diluent are recommended by the manufacturer.

Finally, serum HBsAg may be used as a surrogate for change in liver concentrations of covalently closed circular DNA (cccDNA), and the number of infected cells as suggested in recent studies.12 This is a major issue since cccDNA resides in the nucleus of infected hepatocytes as a stable, resistant and long enduring non-integrated minichromosome, and represents the source of a persisting HBV infection despite undetectability HBV DNA in serum.9 This is emphasized by the data showing that cccDNA levels correlate significantly with the phase of the disease: HBeAg-positive patients have a higher cccDNA copy number per cell than do HBeAg-negative patients, and patients who cleared HBsAg have extremely low levels of cccDNA (0.002 copies/hepatocyte).

In conclusion, serum HBsAg and HBeAg seem to be promising on-treatment quantitative markers for predicting sustained off-treatment response so as to identify during the early phase of peginterferon therapy patients who will most likely benefit from this treatment. Further large studies using peginterferon with or without potent NUC are warranted to confirm these data on a large scale. Future practice guidelines should take into consideration these new benchmarks as promising tools in the management of CHB patients.

References

  1. Top of page
  2. References