The importance of HBV genotype in HBeAg-positive chronic hepatitis B patients in whom sustained response is pursued
Authors: Erik H.C.J. Buster, Harry L.A. Janssen
Journal: Journal of Hepatology (2010)

Is response to antiviral treatment influenced by hepatitis B virus genotype?Journal of HepatologyVol. 52Issue 3PreviewRecently released clinical practice guidelines and consensus conference statements point to the importance of hepatitis B virus (HBV) genotyping in therapeutic algorithms for the treatment of chronic hepatitis B. This information usually comes from post hoc analyses of clinical trials which were not designed to study associations with the HBV genotype. We have performed a literature search through to April 2009 and have selected randomized clinical trials of currently approved anti-HBV drugs providing information on HBV genotypes and (i) baseline characteristics of study subjects, (ii) any response to antiviral therapy, (iii) interaction between HBV genotypes and the type of therapy. Full-Text PDF Open AccessHBV genotype must be included in treatment algorithmJournal of HepatologyVol. 54Issue 2PreviewWe thank Drs. Buster and Janssen for their appreciative comments on our review article recently published in the Journal. We entirely share their views on the important role of HBV genotype in a modern treatment algorithm of patients with chronic HBV infection irrespective of the medicament used, even though, as the authors also reiterated, its effects are indisputably evident only in interferon-treated patients. We also think that a correct algorithm must include histology as an additional variable and that future trials must be powered to detect the effects of other factors, such as age, ALT, and HBV DNA. Full-Text PDF Open Access With great interest we read the review by Raimondi et al. on the influence of hepatitis B virus (HBV) genotype on the outcome of antiviral therapy [[1]Raimondi S. Maisonneuve P. Bruno S. Mondelli M.U. Is response to antiviral treatment influenced by hepatitis B virus genotype?.J Hepatol. 2010; 52: 441-449Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. The authors managed to provide a clear and detailed overview of the available literature on this topic. They conclude that current evidence suggests that potentially better responders to PEG-IFN treatment can be identified by HBV genotyping, while for other antiviral agents clinical trials conducted so far provide insufficient data in order to reach firm conclusions on the role of HBV genotypes in response to antiviral therapy. We fully support the recommendation to perform stratified analyses by ethnic group on available data from large clinical trials, combining the data in a meta-analysis of individual patients, to investigate the possible interactions between the type of therapy and the HBV genotype, or to conduct new clinical trials with sufficient power to detect differences in response rates between HBV genotypes. In fact, we recently performed a pooled analysis of the two largest trials of peginterferon in HBeAg positive hepatitis B. Based on the findings of that study and other studies, we would herein like to emphasize what is in our view the important role of HBV genotype in HBeAg positive patients in whom sustained off-treatment response is pursued. Most studies investigating IFN-based therapy in HBeAg-positive chronic hepatitis B found that high baseline ALT, low baseline HBV DNA, and HBV genotype A or B were associated with a higher chance of response [2Bonino F. Marcellin P. Lau G.K. Hadziyannis S. Jin R. Piratvisuth T. et al.Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B.Gut. 2007; 56: 699-705Crossref PubMed Scopus (239) Google Scholar, 3Cooksley G. Lau G.K.K. Liaw Y.F. Marcellin P. Chow W.C. Thongsawat S. et al.Effects of genotype and other baseline factors on response to peginterferon alfa-2a (40 kDa) (Pegasys®) in HBeAg-positive chronic hepatitis B: results from a large, randomised study.J Hepatol. 2005; 42: S30Google Scholar, 4Craxi A. Di Bona D. Camma C. Interferon-alpha for HBeAg-positive chronic hepatitis B.J Hepatol. 2003; 39: S99-S105Abstract Full Text Full Text PDF PubMed Google Scholar, 5Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar]. In a pooled database of 721 patients from the two largest clinical trials of PEG-IFN in HBeAg-positive chronic hepatitis B we recently found a significant interaction between HBV genotype and sex, age, HBV DNA, and previous IFN therapy [[6]Buster E.H. Hansen B.E. Lau G.K. Piratvisuth T. Zeuzem S. Steyerberg E.W. et al.Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa.Gastroenterology. 2009; 137: 2002-2009Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar]. In fact, HBV genotype was among the strongest predictors of response in addition to HBV DNA and ALT. As mentioned by Raimondi et al. also long-term sustainability of response to PEG-IFN alpha-2b was better in genotype A infected initial responders compared to those with genotype-non-A (96% vs. 71%, p= 0.02), as well as HBsAg loss (58% vs. 11%, p <0.001) [[7]Buster E.H. Flink H.J. Cakaloglu Y. Simon K. Trojan J. Tabak F. et al.Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg positive patients treated with peginterferon alpha-2b.Gastroenterology. 2008; 135: 459-467Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar]. Although one study showed a higher rate of sustained HBeAg seroconversion after therapy in genotype B than genotype C infected lamivudine treated patients [[8]Chien R.N. Yeh C.T. Tsai S.L. Chu C.M. Liaw Y.F. Determinants for sustained HBeAg response to lamivudine therapy.Hepatology (Baltimore, Md.). 2003; 38: 1267-1273Crossref PubMed Scopus (188) Google Scholar], other studies did not find a relation between HBV genotype and on-treatment response to either lamivudine, adefovir or entecavir [9Buti M. Cotrina M. Valdes A. Jardi R. Rodriguez-Frias F. Esteban R. Is hepatitis B virus subtype testing useful in predicting virological response and resistance to lamivudine?.J Hepatol. 2002; 36: 445-446Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 10Lurie Y. Manns M.P. Gish R.G. Chang T.T. Yurdaydin C. Lai C.L. et al.The efficacy of entecavir is similar regardless of disease-related baseline subgroups in treatment of nucleoside-naive, HBeAg(+) and HBeAg(−) patients with chronic hepatitis B.J Hepatol. 2005; 42: 184Google Scholar, 11Yuen M.F. Wong D.K. Sablon E. Yuan H.J. Sum S.M. Hui C.K. et al.Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine.Antivir Ther. 2003; 8: 531-534PubMed Google Scholar]. However, in a pooled analysis of two clinical trials in HBeAg positive patients we did find an association between HBV genotype and sustained off-treatment response to entecavir and PEG-IFN [[12]Buster E.H. Hansen B.E. Verhey E. De Man R.A. Janssen H.L. HBV genotype is an important predictor of sustained off-treatment response to both peginterferon alpha-2b and entecavir in HBeAg positive chronic hepatitis B.Hepatology (Baltimore, MD). 2008; 48: 716AGoogle Scholar]. There was a significant interaction between HBV genotype and the type of antiviral therapy (PEG-IFN α-2b or entecavir). Genotype A and B infected patients had a higher likelihood of sustained virological response to PEG-IFN α-2b than entecavir. Patients infected with genotype C responded equally to PEG-IFN α-2b and entecavir, while genotype D infected patients had a higher chance of achieving sustained virological response with entecavir than PEG-IFN α-2b. Raimondi et al. further suggested that if differences in response to therapy depend on ethnicity, a false-positive association with the HBV genotype may be discovered since overlap between ethnicity and genotype is very high. Since the age of infection is also strongly associated with HBV genotype, this might also be an important factor to consider in that regard. The caveats described by Raimondi et al. may make it difficult to reach firm conclusions on the influence of HBV genotype in response to therapy. However, these caveats do in our opinion also apply for HBV DNA and ALT, while these factors are generally considered to be important predictors of the chance of response to antiviral therapy. We conclude that HBV genotype is in our view an important predictor of response to IFN-based therapy in HBeAg-positive chronic hepatitis B. We therefore recommend determination of HBV genotype in at least all HBeAg positive patients in whom sustained off-treatment response is pursued. The authors who have taken part in this study have declared a relationship with the manufacturers of the drugs involved. Erik H.C.J. Buster- Novartis: speaker’s honoraria; Roche: speaker’s honoraria. Harry L.A. Janssen- Bristol-Myers Squibb: research support, consultancies; Gilead: consultancies, research support; Novartis: research support, consultancies; Roche: research support, consultancies; Schering-Plough: research support.