HBeAg‐positive chronic hepatitis B: why do I treat my patients with pegylated interferon?

Abstract

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).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 longterm 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...

Antiviral Therapies and Prospects for a Cure of Chronic Hepatitis B

“…The efficacy of antiviral drugs has been assessed mainly at 1 year in large randomized controlled trials and has been reviewed recently (EASL 2012;Lampertico and Liaw 2012;Scaglione and Lok 2012;Buti 2014;Kao 2014). Longerterm results are now available from extension of randomized trials, sometime in patient subgroups and from several cohort studies (Hosaka et al 2013;Lai and Yuen 2013;Cho et al 2014;Wu et al 2014).…”

“…Hence, interferon-a (IFN-a) and its pegylated form (Peg-IFN-a), and five other drugs that belong to the class of nucleoside analogs (NAs), have been approved for this indication in most parts of the world (EASL 2012;Lampertico and Liaw 2012;Scaglione and Lok 2012;Jordheim et al 2013;Buti 2014;Kao 2014). IFN-a is an immune modulator that induces, in a nonspecific manner, the expression of interferon-stimulated genes (ISGs) encoding intracellular or secreted proteins with direct or indirect antiviral properties in both infected and noninfected cells, and promotes the differentiation/activation of immune cells (Samuel 2001;Sadler and Williams 2008).…”

“…The therapeutic efficacy of these treatments can be affected by factors, such as the development of adverse effects, poor patient compliance, previous treatment with suboptimal regimens, infection with drug-resistant viral strains, inadequate drug exposure because of pharmacologic properties of particular drug(s), and individual genetic variation (Zoulim 2011;EASL 2012;Gish et al 2012;Lampertico and Liaw 2012;Scaglione and Lok 2012;Buti 2014;Kao 2014). A simplified view of the mode of actions of the approved antiviral agents in the HBV life cycle is shown in Figure 1.…”

“…This is the currently achievable end point, which can be either maintained during therapy or sustained after treatment cessation. However, the ideal end point is HBsAg loss (i.e., HBsAg seroclearance) and/or anti-HBs antibody (i.e., HBsAb) seroconversion, which is currently infrequently achievable with the available anti-HBV agents (EASL 2012;Lampertico and Liaw 2012;Scaglione and Lok 2012;Buti 2014;Kao 2014).…”

“…The international clinical practice guidelines from the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asian Pacific Association for the Study of the Liver (APASL) usually recommend that patients should be considered for treatment when they have HBV DNA levels above 2000 IU/mL, serum ALT levels above the upper limit of normal (ULN), and moderate to severe active necroinflammation and/or at least moderate liver fibrosis severity (EASL 2012;Lampertico and Liaw 2012;Scaglione and Lok 2012;Buti 2014;Kao 2014). Indications for treatment may also take into account age, health status, and family history of cirrhosis or HCC, as well as extrahepatic manifestations of the disease.…”