Is it worthy of switching to PegIFN alfa-2a in patients achieving virological suppression with entecavir?
Authors: Chuanghong Wu, Winston Dunn
Journal: Journal of Hepatology (2015)

Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial)Journal of HepatologyVol. 61Issue 4PreviewDurable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a. Full-Text PDF We read with great interest the article “Switching from entecavir to PegIFN alfa-2a in patients with HBeAg positive chronic hepatitis B: A randomized open-label trial (OSST trial)” [[1]Ning Q. Han M. Sun Y. Jiang J. Tan D. Hou J. et al.Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial).J Hepatol. 2014; 61: 777-784Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar]. This elegant study assessed the rates of HBeAg seroconversion and HBsAg loss in patients with well-controlled HBV DNA replication and serum HBeAg <100 PEIU/ml on long-term entecavir (ETV) therapy after switching to a finite course of PegIFN alfa-2a. Qin Ning et al. [[1]Ning Q. Han M. Sun Y. Jiang J. Tan D. Hou J. et al.Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial).J Hepatol. 2014; 61: 777-784Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar] demonstrated that switching to a finite course of PegIFN alfa-2a significantly increased rates of HBeAg seroconversion and HBsAg loss and concluded this is a potential alternative to indefinite nucleos(t)ide analogue (NA) therapy. Many chronic hepatitis B patients are treated with ETV in China. Some of them hope to stop this infinite treatment if a finite course of treatment can give similar or better outcomes with a reasonable cost and minimal adverse effects. In Shenzhen, patients receiving sequential therapy with NA and PegIFN are not rare. However, there are several concerns about this article and its approach. First, the absolute difference in HBeAg seroconversion rate was only 8.8%. In other words, the number to treat for one HBeAg seroconversion is 11. All these patients have to suffer the adverse effects of PegIFN. It is well known that hepatic decompensation and even death has been reported during IFN treatment. We should also pay special attention to the adverse effect of stopping of ETV. Hepatic decompensation or liver failure was not recorded in the study given the sample size. Recently, one of my patients developed acute on chronic liver failure during PegIFN treatment after stopping ETV and adefovir (ADV) which was reported on in a local hepatology meeting. The effect of an overlapping period of ETV and PegIFN on safety and efficacy remains unclear. Second, the other endpoints of HBV DNA suppression <1000 copies/ml and ALT normalization after 48 weeks of PegIFN treatment was unsatisfactory. These results might be worse after withdrawal of PegIFN therapy. Most of the patients had to resume ETV treatment, which is terrible news for a doctor to have to deliver to patients after a long course of PegIFN therapy. Third, sustained and profound viral suppression is the main goal of treatment. The fluctuation of ALT and HBV DNA in the sequential therapy may mimic the phenomena of viral resistance to NA. It has been reported that treatment related viral resistance blunts histologic responses [[2]Dienstag J.L. Goldin R.D. Heathcote E.J. Hann H.W. Woessner M. Stephenson S.L. et al.Histological outcome during long-term lamivudine therapy.Gastroenterology. 2003; 124: 105-117Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar] and increases the rate of hepatocellular carcinoma (HCC) even if rescue therapy is given [[3]Papatheodoridis G.V. Lampertico P. Manolakopoulos S. Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.J Hepatol. 2010; 53: 348-356Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar]. Fourth, the cost of treatment should also be considered. The per capita disposable income is 18,311 RMB (≈2982 USD) in China 2013. The cost of 48 weeks of PegIFN treatment is about 50,000 RMB (≈8143 USD). Most of the treatment-naïve patients in China may find this treatment unaffordable. The cost of 48 weeks ETV is only one fifth of that. Fifth, the causative agent has not been identified in this randomized controlled study. The treatment arm underwent ETV withdrawal and PegIFN. Withdrawal of ADV after 4–5 years of therapy has been shown to result in 39% HBsAg loss in selected HBeAg negative patients [[4]Hadziyannis S.J. Sevastianos V. Rapti I. Vassilopoulos D. Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg negative patients with chronic hepatitis B who stop long-term treatment with adefovir.Gastroenterology. 2012; 143: 629-636Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar]. To date, there has never been a parallel study in HBeAg positive patients, and there has never been a randomized control trial with PegIFN that involves a control arm with NA withdrawal only. We are anxiously waiting for such a study, we can no longer make the assumption that the treatment effect is entirely due to PegIFN. The correlation between early ALT elevation after withdrawal of ETV with HBeAg seroconversion and HBsAg loss supports this hypothesis. Finally, the benefit of HBeAg seroconversion should not be over emphasized. HBeAg seroconversion has long been regarded as an important treatment endpoint in hepatitis B therapy. However, with the prevalence of pre-core or core mutation HBV infection, HBeAg seroconversion is no longer an ideal endpoint. Recently, Jessica Liu et al. demonstrated that HBV DNA seroclearance, during the course of chronic hepatitis B, is the most significant factor in reducing risk for future HCC and HBeAg seroclearance will not reduce future HCC further [[5]Liu J. Yang H.I. Lee M.H. Lu S.N. Jen C.L. Batrla-Utermann R. et al.Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma.Gut. 2014; 63: 1648-1657Crossref PubMed Scopus (124) Google Scholar]. Combination endpoint with HBeAg seroconversion and HBV DNA <1000 copies/ml may be more reasonable as the primary endpoint. We do not know if the significant difference between the two cohorts was lost with this endpoint. In summary, as clinicians, after weighing the pros and cons, we do not think it is worthy of switching to PegIFN in patients achieving virological suppression with ETV, except if the patient refuse a long-term treatment. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.