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Authors: Daniel Shouval
Journal: Journal of Hepatology (2013)

Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: On-treatment kinetics of HBsAg serum levels vary by HBV genotypeJournal of HepatologyVol. 59Issue 6PreviewWe investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a ± lamivudine in the Phase III trial. Full-Text PDF The hepatitis B surface antigen (HBsAg) is produced by translation of mRNAs of transcriptionally active HBV cccDNA as well as from integrated HBV sequences coding for the surface protein. The clinical utility of HBsAg quantification in monitoring the natural history of chronic hepatitis B (CHB) and in evaluation of response to anti-viral treatment continues to capture the attention of the hepatology community for more than a decade [1Janssen H.L. Kerhof-Los C.J. Heijtink R.A. Schalm S.W. Measurement of HBsAg to monitor hepatitis B viral replication in patients on alpha-interferon therapy.Antiviral Res. 1994; 23: 251-257Crossref PubMed Scopus (51) Google Scholar, 2Deguchi M. Yamashita N. Kagita M. Asari S. Iwatani Y. Tsuchida T. et al.Quantitation of hepatitis B surface antigen by an automated chemiluminescent microparticle immunoassay.J Virol Methods. 2004; 115: 217-222Crossref PubMed Scopus (182) Google Scholar, 3Brunetto M.R. Moriconi F. Bonino F. Lau G.K. Farci P. Yurdaydin C. et al.Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B.Hepatology. 2009; 49: 1141-1150Crossref PubMed Scopus (405) Google Scholar, 4Liaw Y.F. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review.Hepatology. 2011; 54: E1-E9Crossref PubMed Scopus (55) Google Scholar, 5Martinot-Peignoux M. Lapalus M. Asselah T. Marcellin P. The role of HBsAg quantification for monitoring natural history and treatment outcome.Liver Int. 2013; 33: 125-132Crossref PubMed Scopus (57) Google Scholar, 6Tseng T.C. Kao J.H. Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog.J Gastroenterol. 2013; 48: 13-21Crossref PubMed Scopus (96) Google Scholar]. Although at least three standardized immuno-assays for quantification of HBsAg are now commercially available [[7]Chevaliez S. Is HBsAg quantification ready, for prime time?.Clin Res Hepatol Gastroenterol. 2013; ([Epub ahead of print])https://doi.org/10.1016/j.clinre.2013.07.004Crossref PubMed Scopus (9) Google Scholar], its utilization is frequently restricted to academic institutions and research centers. Both HBV-DNA and HBsAg levels fluctuate during the various phases of chronic HBV infection, being high in the initial immune-tolerant phase and usually fading over age except during periods of HBV reactivation. Serum levels of circulating HBsAg are controlled, at least in part, by the amount of intra-hepatic cccHBV-DNA, as well as by specific immune response(s) against the envelope proteins. In general, both HBV-DNA and HBsAg levels are higher in treatment-naïve HBeAg positive as compared to anti-HBe positive CHB patients. In recent years various studies evaluated the utility of HBsAg quantification in assessment of anti-viral response to interferon as well as to nucleot(s)ide analogues. Indeed, it has repeatedly been shown that decreasing HBsAg levels can predict clearance of HBsAg and anti-HBs seroconversion in the relatively small number of patients who resolve the persistent viral infection. Overall, there is already a consensus that in addition to measurements of viral load through HBV-DNA monitoring, HBsAg quantification may be helpful in the prediction of response or non-response to anti-viral treatment for both HBeAg positive and HBeAg negative CHB patients (reviewed in [[5]Martinot-Peignoux M. Lapalus M. Asselah T. Marcellin P. The role of HBsAg quantification for monitoring natural history and treatment outcome.Liver Int. 2013; 33: 125-132Crossref PubMed Scopus (57) Google Scholar]). However, it soon became clear that there seem to be significant geographic variations in the kinetic as well as the positive and negative predictive values of threshold HBsAg levels, which forecast response or non-response to anti-viral treatment especially in HBeAg negative CHB patients treated by pegylated interferon [[8]Marcellin P. Bonino F. Yurdaydin C. Hadziyannis S. Moucari R. Kapprell H.P. et al.Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients.Hepatol Int. 2013; 7: 88-97Crossref PubMed Scopus (119) Google Scholar]. The heterogenous results obtained in different parts of the world suggest that there may be some unrecognized factor(s), which may have an impact on HBsAg levels, before, during and after completion of anti-viral therapy. In the present issue of the Journal, Brunetto and an experienced group of investigators in the field, report the results of a new retrospective analysis of an old multi-center study on the impact of HBV genotypes on the five year kinetics of HBsAg levels in HBeAg negative CHB patients with genotypes A, B, C, and D, treated with pegylated interferon α2a with or without lamivudine [[9]Brunetto M.R. Marcellin P. Cherubini B. Yurdaydin C. Farci P. Hadziyannis S.J. et al.Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype.J Hepatol. 2013; 59: 1153-1159Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. Two cohorts of patients were evaluated: Cohort 1 included 117 patients with available serum samples collected at baseline, week 12, 24, 48, 72 or end of treatment (EOT) as well as at 5 years after completion. Cohort 2 included 199 patients with available serum samples at baseline, EOT and at 5 years. Long-term virologic response was defined as a viral load ⩽×104copies/ml corresponding to 1.78 × 103 IU/ml at 5 years. The major findings of this study suggest that: (1) Baseline HBsAg levels and HBsAg kinetics vary significantly between genotypes tested. For example, baseline HBsAg concentrations were highest in genotype A patients followed by genotype D and lowest for genotypes B and C. In contrast, baseline viral load and ALT levels were similar across genotypes. (2) Patients with genotypes A, D, and B had a heterogenous response to interferon therapy manifested by different slops of HBsAg decline in responders and non-responders while the mean decline of HBsAg concentration was more pronounced across genotypes A, B, and D in responders with long-term viral response as compared to non-responders. In contrast, the almost absent decline in HBsAg levels along time in genotype C patients did not enable distinction between responders and non-responders. (3) The early on-treatment timeframe for recognition of responders following treatment initiation was observed between week 12–24 of treatment for genotype A and between baseline and week 12 for genotype B. Consequently, these observations may facilitate improved definition of treatment stopping rules as suggested recently for interferon treated genotype D patients with lack of HBsAg decline and <2 log10 decrease in viral load at week 12 [[10]Rijckborst V. Hansen B.E. Ferenci P. Brunetto M.R. Tabak F. Cakaloglu Y. et al.Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a.J Hepatol. 2012; 56: 1006-1011Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar]. (4) HBsAg concentration cut-off levels for identification of treatment response as determined by ROC analysis were highest for genotype D at 1000 IU/ml followed by 400 IU/ml for genotype A, 75 IU/ml for genotype C and 50 IU/ml for genotype B. Genotype specific positive predictive cut-off values (PPV) of HBsAg concentration at week 48 and for 5 years post treatment were relatively high for all genotypes tested except for genotype B treated patients. Negative predictive values (NPV) were high irrespective of genotype (see Table 2 [[9]Brunetto M.R. Marcellin P. Cherubini B. Yurdaydin C. Farci P. Hadziyannis S.J. et al.Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype.J Hepatol. 2013; 59: 1153-1159Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]). Comment: The interpretation of this important analysis is indeed complex. Until recently, most reports on utilization of HBsAg quantification did not include a detailed analysis of pre, intra and post treatment response across genotypes. The results of the present study suggest that interpretation obtained through "simple" HBsAg quantification in such patients may not be sufficient and possibly misleading for definition of new stopping rules for treatment. The newly described genotypic cut-off values and variable kinetics of HBsAg may improve our ability to predict the response to and stop (or prolong) of interferon treatment. Yet, as the authors themselves state in their balanced discussion, it seems pre-mature to utilize genotype specific quantification for treatment decisions in HBeAg negative CHB patients. Although original but also intriguing these results require confirmation by a much larger sample size with balanced representation of genotypes before incorporating the conclusions into clinical practice guidelines. The paper by Brunetto et al. [[9]Brunetto M.R. Marcellin P. Cherubini B. Yurdaydin C. Farci P. Hadziyannis S.J. et al.Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype.J Hepatol. 2013; 59: 1153-1159Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar] adds new and important information but is not easy to read. It contains a wealth of additional data not discussed above. The limitations of the analysis are also described in detail in the discussion. HBsAg quantification in clinical practice is still a research tool, which requires more attention from the scientific community. Thus, despite the availability of three excellent commercial assays, the answer to a recent editorial entitled "Is HBsAg quantification ready for prime time?" (7) is: NOT YET. The author declares that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.